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Abstract IA11: New insights into DNA double-strand break responses

Publication ,  Conference
Kastan, MB
Published in: Cancer Research
December 1, 2014

Repair of damaged DNA in cells is complicated by the necessity to repair the damage in the context of complex chromatin structures. Elucidation of molecular mechanisms of DNA repair in intact cells has been challenging. We developed a system that can rapidly induce DNA double strand breaks (DSBs) at defined endogenous sites in mammalian genomes and enables direct assessment of repair and monitoring of protein recruitment, egress, and modification at DSBs in viable cells. The tight regulation of the system also permits assessments of relative kinetics and dependencies of events associated with cellular responses to DNA breakage. Using chromatin immunoprecipitation, we found that nucleosomes are partially disassembled around DSBs during non-homologous end-joining repair in G1-arrested mammalian cells, characterized by a transient loss of the H2A/H2B histone dimer. Nucleolin, a protein with histone chaperone activity, interacts with RAD50 via its RGG domain and is rapidly recruited to DSBs in an MRE11-NBS1-RAD50 complex dependent manner. Down-regulation of nucleolin abrogates the nucleosome disruption, the recruitment of repair factors, and repair of the DSB, demonstrating for the first time the functional importance of nucleosome disruption in DSB repair and identifying a chromatin remodeling protein required for the process. Interestingly, the nucleosome disruption that occurs during DSB repair in cycling cells differs in that both H2A/H2B and H3/H4 histone dimers are removed. This complete nucleosome disruption is also dependent on nucleolin and is required for RPA recruitment to DSBs, a marker of DSB processing that is a requisite for homologous recombination repair. Since inhibition of nucleolin function blunts the DSB repair process, it has become a potential therapeutic target for radiosensitization of tumors. Similarly, small molecule inhibitors of PIKK kinases like ATM and DNA-PK have been developed and are potent radiosensitizers. The potential clinical use of such compounds will be discussed.Citation Format: Michael B. Kastan. New insights into DNA double-strand break responses. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr IA11. doi:10.1158/1538-7445.CANSUSC14-IA11

Duke Scholars

Published In

Cancer Research

DOI

EISSN

1538-7445

ISSN

0008-5472

Publication Date

December 1, 2014

Volume

74

Issue

23_Supplement

Start / End Page

IA11 / IA11

Publisher

American Association for Cancer Research (AACR)

Related Subject Headings

  • Oncology & Carcinogenesis
  • 3211 Oncology and carcinogenesis
  • 3101 Biochemistry and cell biology
  • 1112 Oncology and Carcinogenesis
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Kastan, M. B. (2014). Abstract IA11: New insights into DNA double-strand break responses. In Cancer Research (Vol. 74, pp. IA11–IA11). American Association for Cancer Research (AACR). https://doi.org/10.1158/1538-7445.cansusc14-ia11
Kastan, Michael B. “Abstract IA11: New insights into DNA double-strand break responses.” In Cancer Research, 74:IA11–IA11. American Association for Cancer Research (AACR), 2014. https://doi.org/10.1158/1538-7445.cansusc14-ia11.
Kastan MB. Abstract IA11: New insights into DNA double-strand break responses. In: Cancer Research. American Association for Cancer Research (AACR); 2014. p. IA11–IA11.
Kastan, Michael B. “Abstract IA11: New insights into DNA double-strand break responses.” Cancer Research, vol. 74, no. 23_Supplement, American Association for Cancer Research (AACR), 2014, pp. IA11–IA11. Crossref, doi:10.1158/1538-7445.cansusc14-ia11.
Kastan MB. Abstract IA11: New insights into DNA double-strand break responses. Cancer Research. American Association for Cancer Research (AACR); 2014. p. IA11–IA11.

Published In

Cancer Research

DOI

EISSN

1538-7445

ISSN

0008-5472

Publication Date

December 1, 2014

Volume

74

Issue

23_Supplement

Start / End Page

IA11 / IA11

Publisher

American Association for Cancer Research (AACR)

Related Subject Headings

  • Oncology & Carcinogenesis
  • 3211 Oncology and carcinogenesis
  • 3101 Biochemistry and cell biology
  • 1112 Oncology and Carcinogenesis