Journal ArticleClin Cancer Res · October 25, 2024
BACKGROUND: Preclinical studies have identified molecular correlates of sensitivity to ATR inhibition. This translational study was designed to test the ATR inhibitor berzosertib in patients with advanced solid tumors carrying alterations in ATRX, ATM, gen ...
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Journal ArticleDNA Repair (Amst) · September 2024
Enzymes of the apolipoprotein B mRNA editing catalytic polypeptide like (APOBEC) family are cytosine deaminases that convert cytosine to uracil in DNA and RNA. Among these proteins, APOBEC3 sub-family members, APOBEC3A (A3A) and APOBEC3B (A3B), are promine ...
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Journal ArticleNat Commun · August 28, 2024
EWS fusion oncoproteins underlie several human malignancies including Desmoplastic Small Round Cell Tumor (DSRCT), an aggressive cancer driven by EWS-WT1 fusion proteins. Here we combine chromatin occupancy and 3D profiles to identify EWS-WT1-dependent gen ...
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Journal ArticleMol Cell · June 6, 2024
Alterations of bases in DNA constitute a major source of genomic instability. It is believed that base alterations trigger base excision repair (BER), generating DNA repair intermediates interfering with DNA replication. Here, we show that genomic uracil, ...
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Journal ArticleNat Commun · February 21, 2024
Drugs targeting the DNA damage response (DDR) are widely used in cancer therapy, but resistance to these drugs remains a major clinical challenge. Here, we show that SYCP2, a meiotic protein in the synaptonemal complex, is aberrantly and commonly expressed ...
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Journal ArticleSci Adv · January 19, 2024
Mutation signatures associated with apolipoprotein B mRNA editing catalytic polypeptide-like 3A/B (APOBEC3A/B) cytidine deaminases are prevalent across cancers, implying their roles as mutagenic drivers during tumorigenesis and tumor evolution. APOBEC3A (A ...
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Journal ArticleMol Cell · October 19, 2023
The human ataxia telangiectasia mutated and Rad3-related (ATR) kinase functions in the nucleus to protect genomic integrity. Micronuclei (MN) arise from genomic and chromosomal instability and cause aneuploidy and chromothripsis, but how MN are removed is ...
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Journal ArticleGenes Dev · October 1, 2023
The mismatch repair (MMR) deficiency of cancer cells drives mutagenesis and offers a useful biomarker for immunotherapy. However, many MMR-deficient (MMR-d) tumors do not respond to immunotherapy, highlighting the need for alternative approaches to target ...
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Journal ArticleCancer Res · September 15, 2023
Oncogenic point mutants of isocitrate dehydrogenases 1 and 2 (IDH2) generate 2-hydroxyglutarate, which inhibits lysine demethylases and increases heterochromatin. Tumor cells expressing IDH mutants are sensitive to PARP inhibitors (PARPi), offering an oppo ...
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Journal ArticleNature · August 2023
Acquired drug resistance to anticancer targeted therapies remains an unsolved clinical problem. Although many drivers of acquired drug resistance have been identified1-4, the underlying molecular mechanisms shaping tumour evolution during treatment are inc ...
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Journal ArticleCell Rep · July 25, 2023
The ATR kinase safeguards genomic integrity during S phase, but how ATR protects DNA replication forks remains incompletely understood. Here, we combine four distinct assays to analyze ATR functions at ongoing and newly assembled replication forks upon rep ...
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Journal ArticleNat Commun · January 17, 2023
Prostate cancer harboring BRCA1/2 mutations are often exceptionally sensitive to PARP inhibitors. However, genomic alterations in other DNA damage response genes have not been consistently predictive of clinical response to PARP inhibition. Here, we perfor ...
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Journal ArticleMol Cell · November 3, 2022
Alternative lengthening of telomeres (ALT), a telomerase-independent process maintaining telomeres, is mediated by break-induced replication (BIR). RAD52 promotes ALT by facilitating D-loop formation, but ALT also occurs through a RAD52-independent BIR pat ...
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Journal ArticleSTAR Protoc · September 16, 2022
Alternative lengthening of telomeres (ALT) is a telomerase-independent but recombination-dependent pathway that maintains telomeres. Here, we describe a protocol to stimulate the formation of ALT-associated PML bodies (APBs) and ALT activity by tethering P ...
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Journal ArticleNat Rev Mol Cell Biol · August 2022
RNA-DNA hybrids are generated during transcription, DNA replication and DNA repair and are crucial intermediates in these processes. When RNA-DNA hybrids are stably formed in double-stranded DNA, they displace one of the DNA strands and give rise to a thre ...
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Journal ArticleMol Cell · June 16, 2022
Faithful DNA replication is critical for the maintenance of genomic integrity. Although DNA replication machinery is highly accurate, the process of DNA replication is constantly challenged by DNA damage and other intrinsic and extrinsic stresses throughou ...
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Journal ArticleSci Adv · May 13, 2022
In small cell lung cancer (SCLC), acquired resistance to DNA-damaging therapy is challenging to study because rebiopsy is rarely performed. We used patient-derived xenograft models, established before therapy and after progression, to dissect acquired resi ...
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Journal ArticleJ Invest Dermatol · May 2022
Acral and mucosal melanomas arise from sun-protected sites, disproportionately impact darker-skinned individuals, and exact higher mortality than common types of cutaneous melanoma. Genetically, acral and mucosal melanomas harbor more alterations of KIT th ...
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Journal ArticleNature · May 2022
The entry of mammalian cells into the DNA synthesis phase (S phase) represents a key event in cell division1. According to current models of the cell cycle, the kinase CDC7 constitutes an essential and rate-limiting trigger of DNA replication, acting toget ...
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Journal ArticleProc Natl Acad Sci U S A · March 22, 2022
RNA modifications regulate a variety of cellular processes including DNA repair.The RNA methyltransferase TRDMT1 generates methyl-5-cytosine (m5C) on messen-ger RNA (mRNA) at DNA double-strand breaks (DSBs) in transcribed regions, pro-moting transcription- ...
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Journal ArticleJ Cell Biol · March 7, 2022
RB restricts G1/S progression by inhibiting E2F. Here, we show that sustained expression of active RB, and prolonged G1 arrest, causes visible changes in chromosome architecture that are not directly associated with E2F inhibition. Using FISH probes agains ...
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Journal ArticleGenes Dev · March 1, 2022
DNA repair and DNA damage signaling pathways are critical for the maintenance of genomic stability. Defects of DNA repair and damage signaling contribute to tumorigenesis, but also render cancer cells vulnerable to DNA damage and reliant on remaining repai ...
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Journal ArticleSci Adv · February 18, 2022
Current targeted cancer therapies are largely guided by mutations of a single gene, which overlooks concurrent genomic alterations. Here, we show that RNASEH2B, RB1, and BRCA2, three closely located genes on chromosome 13q, are frequently deleted in prosta ...
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Journal ArticleCell Rep · February 1, 2022
Single-stranded DNA (ssDNA) arising as an intermediate of cellular processes on DNA is a potential vulnerability of the genome unless it is appropriately protected. Recent evidence suggests that R-loops, consisting of ssDNA and DNA-RNA hybrids, can form in ...
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Journal ArticleCurr Opin Genet Dev · December 2021
The maintenance of genomic integrity relies on the coordination of a wide range of cellular processes and efficient repair of DNA damage. Since its discovery over two decades ago, the ATR kinase has been recognized as the master regulator of the circuitry ...
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Journal ArticleNat Commun · October 13, 2021
The BRCA2 tumor suppressor protects genome integrity by promoting homologous recombination-based repair of DNA breaks, stability of stalled DNA replication forks and DNA damage-induced cell cycle checkpoints. BRCA2 deficient cells display the radio-resista ...
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Journal ArticleMol Cell · October 7, 2021
PRIMPOL repriming allows DNA replication to skip DNA lesions, leading to ssDNA gaps. These gaps must be filled to preserve genome stability. Using a DNA fiber approach to directly monitor gap filling, we studied the post-replicative mechanisms that fill th ...
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Journal ArticleGenes Dev · September 1, 2021
PARP inhibitor (PARPi) is widely used to treat BRCA1/2-deficient tumors, but why PARPi is more effective than other DNA-damaging drugs is unclear. Here, we show that PARPi generates DNA double-strand breaks (DSBs) predominantly in a trans cell cycle manner ...
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Journal ArticleDNA Repair (Amst) · September 2021
The proper spatial organization of DNA, RNA, and proteins is critical for a variety of cellular processes. The genome is organized into numerous functional units, such as topologically associating domains (TADs), the formation of which is regulated by both ...
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Journal ArticleNature · June 2021
Homologous recombination (HR) repairs DNA double-strand breaks (DSBs) in the S and G2 phases of the cell cycle1-3. Several HR proteins are preferentially recruited to DSBs at transcriptionally active loci4-10, but how transcription promotes HR is poorly un ...
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Journal ArticleElife · April 23, 2021
The FOXM1 transcription factor is an oncoprotein and a top biomarker of poor prognosis in human cancer. Overexpression and activation of FOXM1 is frequent in high-grade serous carcinoma (HGSC), the most common and lethal form of human ovarian cancer, and i ...
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Journal ArticleNat Commun · March 11, 2021
APOBEC mutagenesis, a major driver of cancer evolution, is known for targeting TpC sites in DNA. Recently, we showed that APOBEC3A (A3A) targets DNA hairpin loops. Here, we show that DNA secondary structure is in fact an orthogonal influence on A3A substra ...
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Journal ArticleMol Cell · March 4, 2021
Alternative lengthening of telomeres (ALT) is mediated by break-induced replication (BIR), but how BIR is regulated at telomeres is poorly understood. Here, we show that telomeric BIR is a self-perpetuating process. By tethering PML-IV to telomeres, we ind ...
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Journal ArticleMol Cell · February 18, 2021
DNA replication forks use multiple mechanisms to deal with replication stress, but how the choice of mechanisms is made is still poorly understood. Here, we show that CARM1 associates with replication forks and reduces fork speed independently of its methy ...
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Journal ArticleSci Rep · February 11, 2021
Mutant KRAS is a common tumor driver and frequently confers resistance to anti-cancer treatments such as radiation. DNA replication stress in these tumors may constitute a therapeutic liability but is poorly understood. Here, using single-molecule DNA fibe ...
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Journal ArticleSci Adv · October 2020
The cyclic GMP-AMP synthase (cGAS), a sensor of cytosolic DNA, is critical for the innate immune response. Here, we show that loss of cGAS in untransformed and cancer cells results in uncontrolled DNA replication, hyperproliferation, and genomic instabilit ...
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Journal ArticleCancer Res · September 15, 2020
Inactivation of SMARCA4/BRG1, the core ATPase subunit of mammalian SWI/SNF complexes, occurs at very high frequencies in non-small cell lung cancers (NSCLC). There are no targeted therapies for this subset of lung cancers, nor is it known how mutations in ...
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Journal ArticleSci Adv · July 2020
Despite considerable efforts, mTOR inhibitors have produced limited success in the clinic. To define the vulnerabilities of mTORC1-addicted cancer cells and to find previously unknown therapeutic targets, we investigated the mechanism of piperlongumine, a ...
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Journal ArticleGenes Dev · July 1, 2020
R loops arise from hybridization of RNA transcripts with template DNA during transcription. Unrepaired R loops lead to transcription-replication collisions, causing DNA damage and genomic instability. In this issue of Genes & Development, Pérez-Calero and ...
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Journal ArticleNat Commun · June 12, 2020
APOBEC3A is a cytidine deaminase driving mutagenesis, DNA replication stress and DNA damage in cancer cells. While the APOBEC3A-induced vulnerability of cancers offers an opportunity for therapy, APOBEC3A protein and mRNA are difficult to quantify in tumor ...
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Journal ArticleNat Commun · June 5, 2020
Recruitment of DNA repair proteins to DNA damage sites is a critical step for DNA repair. Post-translational modifications of proteins at DNA damage sites serve as DNA damage codes to recruit specific DNA repair factors. Here, we show that mRNA is locally ...
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Journal ArticleNucleic Acids Res · February 20, 2020
Reactive oxygen species (ROS) inflict multiple types of lesions in DNA, threatening genomic integrity. How cells respond to ROS-induced DNA damage at telomeres is still largely unknown. Here, we show that ROS-induced DNA damage at telomeres triggers R-loop ...
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Journal ArticleMol Cell · February 6, 2020
R loops arising during transcription induce genomic instability, but how cells respond to the R loop-associated genomic stress is still poorly understood. Here, we show that cells harboring high levels of R loops rely on the ATR kinase for survival. In res ...
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Journal ArticleTher Adv Med Oncol · 2020
BACKGROUND: Ataxia-telangiectasia and Rad3 related protein kinase (ATR) is an essential regulator of the DNA damage response in various cancers; however, its expression and roles in osteosarcoma are unclear. We therefore chose to evaluate the significance ...
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Journal ArticleCell Biosci · 2020
To escape replicative senescence, cancer cells have to overcome telomere attrition during DNA replication. Most of cancers rely on telomerase to extend and maintain telomeres, but 4-11% of cancers use a homologous recombination-based pathway called alterna ...
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Journal ArticleCancer Cell · November 11, 2019
In this issue of Cancer Cell, Quereda and colleagues report that a newly developed specific inhibitor of CDK12/13, SR-4835, sensitizes triple-negative breast cancer cells to PARP inhibitors and DNA-damaging chemotherapeutics by reducing expression of the g ...
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Journal ArticleClin Cancer Res · October 15, 2019
PURPOSE: PARP inhibitors are approved for the treatment of high-grade serous ovarian cancers (HGSOC). Therapeutic resistance, resulting from restoration of homologous recombination (HR) repair or replication fork stabilization, is a pressing clinical probl ...
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Journal ArticleOncologist · October 2019
BACKGROUND: Alterations in the DNA damage response (DDR) pathway confer sensitivity to certain chemotherapies, radiation, and other DNA damage repair targeted therapies. BRCA1/2 are the most well-studied DDR genes, but recurrent alterations are described i ...
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Journal ArticleCell Rep · July 9, 2019
DNA damage activates checkpoints that limit the replicative potential of stem cells, including differentiation. These checkpoints protect against cancer development but also promote tissue aging. Because mice lacking Slug/Snai2 exhibit limited stem cell ac ...
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Journal ArticleNat Commun · July 2, 2019
PARP inhibitors (PARPis) have clinical efficacy in BRCA-deficient cancers, but not BRCA-intact tumors, including glioblastoma (GBM). We show that MYC or MYCN amplification in patient-derived glioblastoma stem-like cells (GSCs) generates sensitivity to PARP ...
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Journal ArticleScience · June 28, 2019
Cancer drivers require statistical modeling to distinguish them from passenger events, which accumulate during tumorigenesis but provide no fitness advantage to cancer cells. The discovery of driver genes and mutations relies on the assumption that exact p ...
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Journal ArticleMol Cell · June 20, 2019
In this issue, Li et al. (2019) report a previously unknown Ca2+-CaMKK2-AMPK signaling cascade that protects stalled forks from degradation by phosphorylating and inhibiting the EXO1 nuclease, revealing a surprising role for Ca2+ influx in the maintenance ...
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Journal ArticleHepatology · June 2019
Replication fork stability during DNA replication is vital for maintenance of genomic stability and suppression of cancer development in mammals. ATR (ataxia-telangiectasia mutated [ATM] and RAD3-related) is a master regulatory kinase that activates the re ...
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Journal ArticleCell Rep · January 22, 2019
Alternative lengthening of telomeres (ALT) is a telomerase-independent but recombination-dependent pathway that maintains telomeres. Here, we describe an assay to visualize ALT-mediated telomeric DNA synthesis in ALT-associated PML bodies (APBs) without DN ...
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Journal ArticleGenes Dev · January 1, 2019
Numerous DNA repair and signaling proteins function at DNA damage sites to protect the genome. Here, we show that fusion of the promiscuous biotin ligase BirAR118G with RAD18 leads to localized protein biotinylation at DNA damage sites, allowing identifica ...
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Journal ArticleMol Cell · October 18, 2018
DNA replication forks collapse at numerous sites throughout the genome under replication stress. Studies by Shastri et al. (2018) and Tubbs et al. (2018) used different genomics approaches to map the sites of replication fork collapse, revealing the contri ...
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Journal ArticleNat Commun · October 8, 2018
Actively transcribed regions of the genome are protected by transcription-coupled DNA repair mechanisms, including transcription-coupled homologous recombination (TC-HR). Here we used reactive oxygen species (ROS) to induce and characterize TC-HR at a tran ...
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Journal ArticleCancer Res · September 15, 2018
Heterozygous somatic mutations in spliceosome genes (U2AF1, SF3B1, ZRSR2, or SRSF2) occur in >50% of patients with myelodysplastic syndrome (MDS). These mutations occur early in disease development, suggesting that they contribute to MDS pathogenesis and m ...
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Journal ArticleScience · January 5, 2018
The ataxia telangiectasia mutated and Rad3-related (ATR) kinase is crucial for DNA damage and replication stress responses. Here, we describe an unexpected role of ATR in mitosis. Acute inhibition or degradation of ATR in mitosis induces whole-chromosome m ...
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Journal ArticleDev Cell · December 18, 2017
To understand the consequences of the complete elimination of E2F regulation, we profiled the proteome of Drosophila dDP mutants that lack functional E2F/DP complexes. The results uncovered changes in the larval fat body, a differentiated tissue that grows ...
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Journal ArticleNat Commun · October 16, 2017
The breast cancer susceptibility proteins BRCA1 and BRCA2 have emerged as key stabilizing factors for the maintenance of replication fork integrity following replication stress. In their absence, stalled replication forks are extensively degraded by the MR ...
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Journal ArticleSci China Life Sci · October 2017
Repair of DNA double-strand breaks (DSBs) via the homologous recombination (HR) pathway is a highly regulated process. A number of proteins that participate in HR are intricately modulated by the cell cycle and chromatin environments of DSBs. Recent studie ...
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Journal ArticleNucleic Acids Res · September 6, 2017
RPA-coated single-stranded DNA (RPA-ssDNA), a nucleoprotein structure induced by DNA damage, promotes ATR activation and homologous recombination (HR). RPA is hyper-phosphorylated and ubiquitylated after DNA damage. The ubiquitylation of RPA by PRP19 and R ...
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Journal ArticleCancer Res · September 1, 2017
The apolipoprotein B mRNA editing enzyme catalytic polypeptide-like APOBEC3A and APOBEC3B have emerged as key mutation drivers in cancer. Here, we show that APOBEC3A and APOBEC3B activities impose a unique type of replication stress by inducing abasic site ...
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Journal ArticleJ Clin Invest · May 1, 2017
Many cancer-associated mutations that deregulate cellular metabolic responses to hypoxia also reprogram carbon metabolism to promote utilization of glutamine. In renal cell carcinoma (RCC), cells deficient in the von Hippel-Lindau (VHL) tumor suppressor ge ...
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Journal ArticleNature · March 23, 2017
Cell proliferation and survival require the faithful maintenance and propagation of genetic information, which are threatened by the ubiquitous sources of DNA damage present intracellularly and in the external environment. A system of DNA repair, called th ...
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Journal ArticleMol Cell · March 2, 2017
R loop, a transcription intermediate containing RNA:DNA hybrids and displaced single-stranded DNA (ssDNA), has emerged as a major source of genomic instability. RNaseH1, which cleaves the RNA in RNA:DNA hybrids, plays an important role in R loop suppressio ...
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Journal ArticleGenes Dev · February 1, 2017
Poly-(ADP-ribose) polymerase (PARP) inhibitors (PARPis) selectively kill BRCA1/2-deficient cells, but their efficacy in BRCA-deficient patients is limited by drug resistance. Here, we used derived cell lines and cells from patients to investigate how to ov ...
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Journal ArticleMol Cell · January 19, 2017
ATR is a key regulator of cell-cycle checkpoints and homologous recombination (HR). Paradoxically, ATR inhibits CDKs during checkpoint responses, but CDK activity is required for efficient HR. Here, we show that ATR promotes HR after CDK-driven DNA end res ...
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Journal ArticleCurr Biol · January 9, 2017
The ATR kinase is a master regulator of replication stress responses. Four new studies show that the protein ETAA1 is an important activator of ATR in human cells, providing insights into how the ATR pathway reacts to replication stress. ...
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Journal ArticleCell · December 15, 2016
DNA demethylation, a process involving DNA repair, is critical for reprogramming of the paternal genome during the oocyte-to-zygote transition. A new study by Ladstätter and Tachibana-Konwalski shows that a Chk1-mediated zygotic checkpoint monitors the coh ...
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Journal ArticleAnnu Rev Genet · November 23, 2016
The ATR (ATM and rad3-related) pathway is crucial for proliferation, responding to DNA replication stress and DNA damage. This critical signaling pathway is carefully orchestrated through a multistep process requiring initial priming of ATR prior to damage ...
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Journal ArticleCancer Discov · July 2016
UNLABELLED: Cancer genome characterization efforts now provide an initial view of the somatic alterations in primary tumors. However, most point mutations occur at low frequency, and the function of these alleles remains undefined. We have developed a scal ...
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Journal ArticleJ Biol Chem · January 1, 2016
The maintenance of genomic stability relies on the concerted action of DNA repair and DNA damage signaling pathways. The PIAS (protein inhibitor of activated STAT) family of SUMO (small ubiquitin-like modifier) ligases has been implicated in DNA repair, bu ...
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Chapter · January 1, 2016
DNA replication is one of the most fundamental cellular processes. Faithful replication of the entire genome is a daunting task, especially when cells are under intrinsic or extrinsic stress. To maintain genomic stability during DNA replication, eukaryotic ...
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Journal ArticleNat Commun · December 15, 2015
The Set8/PR-Set7/KMT5a methyltransferase plays critical roles in governing transcriptional regulation, cell cycle progression and tumorigenesis. Although CRL4(Cdt2) was reported to regulate Set8 stability, deleting the PIP motif only led to partial resista ...
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Journal ArticleClin Cancer Res · November 1, 2015
The human ATR gene encodes a kinase that is activated by DNA damage and replication stress as a central transducer of a checkpoint signaling pathway. Once activated, ATR phosphorylates multiple substrates, including the kinase Chk1, to regulate cell-cycle ...
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Journal ArticleMol Cell · September 17, 2015
The ATR-Chk1 pathway is critical for DNA damage responses and cell-cycle progression. Chk1 inhibition is more deleterious to cycling cells than ATR inhibition, raising questions about ATR and Chk1 functions in the absence of extrinsic replication stress. H ...
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Journal ArticleJ Biol Chem · June 12, 2015
Circulating tumor cells (CTCs) are seeds for cancer metastasis and are predictive of poor prognosis in breast cancer patients. Whether CTCs and primary tumor cells (PTCs) respond to chemotherapy differently is not known. Here, we show that CTCs of breast c ...
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Journal ArticleScience · January 16, 2015
Cancer cells rely on telomerase or the alternative lengthening of telomeres (ALT) pathway to overcome replicative mortality. ALT is mediated by recombination and is prevalent in a subset of human cancers, yet whether it can be exploited therapeutically rem ...
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Journal ArticleMol Cell · January 8, 2015
SLX4, a coordinator of multiple DNA structure-specific endonucleases, is important for several DNA repair pathways. Noncovalent interactions of SLX4 with ubiquitin are required for localizing SLX4 to DNA interstrand crosslinks (ICLs), yet how SLX4 is targe ...
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Journal ArticleCell Res · January 2015
The Replication Protein A (RPA) complex is an essential regulator of eukaryotic DNA metabolism. RPA avidly binds to single-stranded DNA (ssDNA) through multiple oligonucleotide/oligosaccharide-binding folds and coordinates the recruitment and exchange of g ...
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Journal ArticleCell Rep · August 7, 2014
Germline mutations of BRCA1 confer hereditary susceptibility to breast and ovarian cancer. However, somatic mutation of BRCA1 is infrequent in sporadic breast cancers. The BRCA1 protein C terminus (BRCT) domains interact with multiple proteins and are requ ...
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Journal ArticleGenes Dev · July 1, 2014
The ATR (ATM [ataxia telangiectasia-mutated]- and Rad3-related) checkpoint is a crucial DNA damage signaling pathway. While the ATR pathway is known to transmit DNA damage signals through the ATR-Chk1 kinase cascade, whether post-translational modification ...
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Journal ArticleMol Cell · March 20, 2014
Chromosome instability (CIN), a common feature of solid tumors, promotes tumor evolution and increases drug resistance during therapy. We previously demonstrated that loss of the retinoblastoma protein (pRB) tumor suppressor causes changes in centromere st ...
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Journal ArticleMol Cell · January 23, 2014
PRP19 is a ubiquitin ligase involved in pre-mRNA splicing and the DNA damage response (DDR). Although the role for PRP19 in splicing is well characterized, its role in the DDR remains elusive. Through a proteomic screen for proteins that interact with RPA- ...
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Journal ArticleCarcinogenesis · November 2013
Inhibitors of poly(ADP-ribose) polymerase (PARP) are promising anticancer drugs, particularly for the treatment of tumors deficient in the DNA damage response (DDR). However, it is challenging to design effective therapeutic strategies for use of these com ...
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Journal ArticleCancer Res · October 15, 2013
In patients with lung cancer whose tumors harbor activating mutations in the EGF receptor (EGFR), increased responses to platinum-based chemotherapies are seen compared with wild-type cancers. However, the mechanisms underlying this association have remain ...
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Journal ArticleCold Spring Harb Perspect Biol · September 1, 2013
In eukaryotic cells, maintenance of genomic stability relies on the coordinated action of a network of cellular processes, including DNA replication, DNA repair, cell-cycle progression, and others. The DNA damage response (DDR) signaling pathway orchestrat ...
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Journal ArticleCell Rep · May 30, 2013
The ATM- and Rad3-related (ATR) kinase is a master regulator of the DNA damage response, yet how ATR is activated toward different substrates is still poorly understood. Here, we show that ATR phosphorylates Chk1 and RPA32 through distinct mechanisms at re ...
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Journal ArticleJ Thorac Oncol · March 2013
INTRODUCTION: Homologous recombination repair (HRR) is a critical pathway for the repair of DNA damage caused by cisplatin or poly-ADP ribose polymerase (PARP) inhibitors. HRR may be impaired by multiple mechanisms in cancer, which complicates assessing th ...
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Journal ArticleProc Natl Acad Sci U S A · February 5, 2013
The master checkpoint kinase ATR (ATM and Rad3-related) and its partner ATRIP (ATR-interacting protein) exist as a complex and function together in the DNA damage response. Unexpectedly, we found that the stability of the ATR-ATRIP complex is regulated by ...
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Journal ArticleGenes Dev · February 1, 2013
The yeast Mec1 kinase is a key regulator of the DNA damage response (DDR). In this issue of Genes & Development, Kumar and Burgers (pp. 313-321) report that Ddc1, Dpb11, and Dna2 function in concert to activate Mec1 during S phase of the cell cycle. Furthe ...
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Journal ArticleCell Cycle · July 15, 2012
Claspin is a key mediator of the ATR-Chk1 checkpoint pathway. In response to DNA damage, Claspin interacts with Rad17 and Chk1 in a phosphorylation-dependent manner, enabling ATR to phosphorylate Chk1 efficiently. Claspin also interacts with Rad9, but how ...
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Journal ArticleMol Cell · June 8, 2012
PCNA is a key component of DNA replication and repair machineries. DNA damage-induced PCNA ubiquitylation serves as a molecular mark to orchestrate postreplication repair. Here, we have identified and characterized Spartan, a protein that specifically reco ...
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Journal ArticleJ Biol Chem · March 30, 2012
The E3 ubiquitin ligase Cullin-ring ligase 4-Cdt2 (CRL4(Cdt2)) is emerging as an important cell cycle regulator that targets numerous proteins for destruction in S phase and after DNA damage, including Cdt1, p21, and Set8. CRL4(Cdt2) substrates contain a " ...
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Journal ArticleProc Natl Acad Sci U S A · February 21, 2012
Homeobox 9 (HOXB9), a nontransforming transcription factor overexpressed in breast cancer, alters tumor cell fate and promotes tumor progression and metastasis. Here we show that HOXB9 confers resistance to ionizing radiation by promoting DNA damage respon ...
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Journal ArticleCell Cycle · February 15, 2012
Telomere maintenance in cycling cells relies on both DNA replication and capping by the protein complex shelterin. Two single-stranded DNA (ssDNA)-binding proteins, replication protein A (RPA) and protection of telomere 1 (POT1) play critical roles in DNA ...
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Journal ArticleMol Cell · September 2, 2011
Translesion DNA synthesis, a process orchestrated by monoubiquitinated PCNA, is critical for DNA damage tolerance. While the ubiquitin-conjugating enzyme RAD6 and ubiquitin ligase RAD18 are known to monoubiquitinate PCNA, how they are regulated by DNA dama ...
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Journal ArticleMol Cell · July 22, 2011
The ataxia telangiectasia-mutated and Rad3-related (ATR) kinase is a master checkpoint regulator safeguarding the genome. Upon DNA damage, the ATR-ATRIP complex is recruited to sites of DNA damage by RPA-coated single-stranded DNA and activated by an elusi ...
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Journal ArticleCancer Research · April 15, 2011
AbstractThe Mammalian Target of Rapamycin is a highly conserved Serine/Threonine protein kinase that plays a key role in several fundamental cellular processes such as growth, proliferation and metabolism. A ...
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Journal ArticleNature · March 24, 2011
Maintenance of telomeres requires both DNA replication and telomere 'capping' by shelterin. These two processes use two single-stranded DNA (ssDNA)-binding proteins, replication protein A (RPA) and protection of telomeres 1 (POT1). Although RPA and POT1 ea ...
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Journal ArticleMol Cell · March 4, 2011
The E3 ubiquitin ligase RNF20 regulates chromatin structure by monoubiquitinating histone H2B in transcription. Here, we show that RNF20 is localized to double-stranded DNA breaks (DSBs) independently of H2AX and is required for the DSB-induced H2B ubiquit ...
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Journal ArticleTrends Biochem Sci · March 2011
The integrity of the genome is constantly challenged by intrinsic and extrinsic genotoxic stresses that damage DNA. The cellular responses to DNA damage are orchestrated by DNA damage signaling pathways, also known as DNA damage checkpoints. These signalin ...
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Journal ArticlePLoS One · 2011
Homologous recombination (HR) is required for the restart of collapsed DNA replication forks and error-free repair of DNA double-strand breaks (DSB). However, unscheduled or hyperactive HR may lead to genomic instability and promote cancer development. The ...
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Journal ArticleMethods Mol Biol · 2011
The Ataxia telangiectasia-mutated (ATM) and the ATM-Rad3-related (ATR) kinases are master regulators of the DNA damage-signaling pathways that respond to a wide variety of DNA damage. In this chapter, we describe an in vitro biochemical assay to study the ...
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Journal ArticleMol Cell · October 8, 2010
The proper coordination between DNA replication and mitosis during cell-cycle progression is crucial for genomic stability. During G2 and mitosis, Set8 catalyzes monomethylation of histone H4 on lysine 20 (H4K20me1), which promotes chromatin compaction. Se ...
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Journal ArticleCrit Rev Biochem Mol Biol · August 2010
The maintenance of genomic stability relies on the coordinated action of a number of cellular processes, including activation of the DNA-damage checkpoint, DNA replication, DNA repair, and telomere homeostasis. Many proteins involved in these cellular proc ...
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Journal ArticleMol Cell · July 30, 2010
Cells from Fanconi anemia (FA) patients are extremely sensitive to DNA interstrand crosslinking (ICL) agents, but the molecular basis of the hypersensitivity remains to be explored. FANCM (FA complementation group M), and its binding partner, FAAP24, ancho ...
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Journal ArticleCell · April 2, 2010
Accumulating evidence implicates heterogeneity within cancer cell populations in the response to stressful exposures, including drug treatments. While modeling the acute response to various anticancer agents in drug-sensitive human tumor cell lines, we con ...
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Journal ArticleMol Cell · December 11, 2009
In this issue of Molecular Cell, Navadgi-Patil and Burgers show that the budding yeast Mec1 kinase is activated by DNA damage through two distinct Ddc1-mediated mechanisms during G1 and G2 phases of the cell cycle. ...
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Journal ArticleMol Cancer Res · September 2009
Mutational inactivation of genes controlling the DNA-damage response contributes to cancer susceptibility within families and within the general population as well as to sporadic tumorigenesis. Claspin (CLSPN) encodes a recently recognized mediator protein ...
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Journal ArticleMol Cell · March 13, 2009
ATM and ATR are two master checkpoint kinases activated by double-stranded DNA breaks (DSBs). ATM is critical for the initial response and the subsequent ATR activation. Here we show that ATR activation is coupled with loss of ATM activation, an unexpected ...
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Journal ArticleCell Cycle · January 15, 2009
During cell proliferation, DNA damage inflicted by intrinsic or extrinsic genotoxic stresses impose a threat to DNA replication. The stability of the DNA replication forks that encounter DNA damage is crucial for genomic integrity. Both the ATR-regulated c ...
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Journal ArticleGenes Dev · May 1, 2008
Chk1 is a kinase crucial for genomic integrity and an effector of ATR (ATM and Rad3-related) in DNA damage response. Here, we show that Chk1 regulates the DNA damage-induced ubiquitination of proliferating cell nuclear antigen (PCNA), which facilitates the ...
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Journal ArticleMol Cell · August 4, 2006
The ATR-mediated checkpoint is not only critical for responding to genotoxic stress but also essential for cell proliferation. The RFC-related checkpoint protein Rad17, a phosphorylation substrate of ATR, is critical for ATR-mediated checkpoint signaling a ...
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Journal ArticleProc Natl Acad Sci U S A · January 17, 2006
The ATR (ATM- and rad3-related)-mediated checkpoint pathway has a crucial role in regulating the cellular responses to DNA damage and DNA-replication stress. ATRIP (ATR-interacting protein), the regulatory partner of ATR, binds directly to replication prot ...
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Journal ArticleMethods Enzymol · 2006
The ATR (ataxia-telangiectasia mutated and rad3-related)-ATRIP (ATR-interacting protein) kinase complex plays a central role in the checkpoint responses to a variety of types of DNA damage, especially those interfering with DNA replication. The checkpoint- ...
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Journal ArticleResults Probl Cell Differ · 2006
The DNA damage and replication checkpoints are signaling mechanisms that regulate and coordinate cellular responses to genotoxic conditions. The activation of checkpoints not only attenuates cell cycle progression, but also facilitates DNA repair and recov ...
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Journal ArticleJ Cell Biochem · February 1, 2005
The DNA damage and replication checkpoints are signaling mechanisms that regulate and coordinate cellular responses to genotoxic conditions. Unlike typical signal transduction mechanisms that respond to one or a few stimuli, checkpoints can be activated by ...
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Journal ArticleProceedings of the National Academy of Sciences · November 25, 2003
The human Rad17–Rfc2-5 and Rad9–Rad1–Hus1 complexes play crucial roles in the activation of the ATR-mediated DNA damage and DNA replication stress response pathways. In response to DNA damage, Rad9 is recruited to chromatin in a Rad17- ...
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Journal ArticleScience · June 6, 2003
The function of the ATR (ataxia-telangiectasia mutated– and Rad3-related)–ATRIP (ATR-interacting protein) protein kinase complex is crucial for the cellular response to replication stress and DNA damage. Here, we show that replication ...
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Journal ArticleGenes & Development · January 15, 2002
Cells respond to DNA damage by activating a network of signaling pathways that control cell cycle progression and DNA repair. Genetic studies in yeast suggested that several checkpoint proteins, including the RFC-related Rad17 protein, and the PCNA ...
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Journal ArticleElectrophoresis · August 2000
The two protein components of nitrogenase from Klebsiella pneumoniae were shown to interact with metal ions and ADP, altering their electrophoretic mobility in polyacrylamide gel electrophoresis. Both Mg+2 and Mn+2 caused reduced mobility of Fe protein rel ...
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Journal ArticleMol Cell Biol · May 2000
In Saccharomyces cerevisiae, replication origins are activated with characteristic timing during S phase. S-phase cyclin-dependent kinases (S-CDKs) and Cdc7p-Dbf4p kinase are required for origin activation throughout S phase. The activation of S-CDKs leads ...
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Journal ArticleProtein Sci · January 2000
The nitrogenase enzyme of Klebsiella pneumoniae consists of two separable proteins, each with multiple subunits and one or more oxygen sensitive metallocenters. The wild-type nitrogenase proteins are stable to electrophoresis in high concentrations of urea ...
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Journal ArticleScience · April 24, 1998
Cdc45p, a protein essential for initiation of DNA replication, associates with chromatin after "start" in late G1 and during the S phase of the cell cycle. Binding of Cdc45p to chromatin depends on Clb-Cdc28 kinase activity as well as functional Cdc6p and ...
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Journal ArticleMol Cell Biol · February 1997
The CDC45 gene of Saccharomyces cerevisiae was isolated by complementation of the cold-sensitive cdc45-1 mutant and shown to be essential for cell viability. Although CDC45 genetically interacts with a group of MCM genes (CDC46, CDC47, and CDC54), the pred ...
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