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Repair versus Checkpoint Functions of BRCA1 Are Differentially Regulated by Site of Chromatin Binding.

Publication ,  Journal Article
Goldstein, M; Kastan, MB
Published in: Cancer Res
July 1, 2015

The product of the Brca1 tumor-suppressor gene is involved in multiple aspects of the cellular DNA damage response (DDR), including activation of cell-cycle arrests and DNA double-stranded break (DSB) repair by homologous recombination. Prior reports demonstrated that BRCA1 recruitment to areas of DNA breakage depended on RAP80 and the RNF8/RNF168 E3 ubiquitin ligases. Here, we extend these findings by showing that RAP80 is only required for the binding of BRCA1 to regions flanking the DSB, whereas BRCA1 binding directly to DNA breaks requires Nijmegen breakage syndrome 1 (NBS1). These differential recruitment mechanisms differentially affect BRCA1 functions: (i) RAP80-dependent recruitment of BRCA1 to chromatin flanking DNA breaks is required for BRCA1 phosphorylation at serine 1387 and 1423 by ATM and, consequently, for the activation of S and G(2) checkpoints; and (ii) BRCA1 interaction with NBS1 upon DSB induction results in an NBS1-dependent recruitment of BRCA1 directly to the DNA break and is required for nonhomologous end-joining repair. Together, these findings illustrate that spatially distinct fractions of BRCA1 exist at the DSB site, which are recruited by different mechanisms and execute different functions in the DDR.

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Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

July 1, 2015

Volume

75

Issue

13

Start / End Page

2699 / 2707

Location

United States

Related Subject Headings

  • Ubiquitin-Protein Ligases
  • S Phase Cell Cycle Checkpoints
  • Oncology & Carcinogenesis
  • Nuclear Proteins
  • MCF-7 Cells
  • M Phase Cell Cycle Checkpoints
  • Humans
  • Histone Chaperones
  • Hela Cells
  • HeLa Cells
 

Citation

APA
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ICMJE
MLA
NLM
Goldstein, M., & Kastan, M. B. (2015). Repair versus Checkpoint Functions of BRCA1 Are Differentially Regulated by Site of Chromatin Binding. Cancer Res, 75(13), 2699–2707. https://doi.org/10.1158/0008-5472.CAN-15-0400
Goldstein, Michael, and Michael B. Kastan. “Repair versus Checkpoint Functions of BRCA1 Are Differentially Regulated by Site of Chromatin Binding.Cancer Res 75, no. 13 (July 1, 2015): 2699–2707. https://doi.org/10.1158/0008-5472.CAN-15-0400.
Goldstein, Michael, and Michael B. Kastan. “Repair versus Checkpoint Functions of BRCA1 Are Differentially Regulated by Site of Chromatin Binding.Cancer Res, vol. 75, no. 13, July 2015, pp. 2699–707. Pubmed, doi:10.1158/0008-5472.CAN-15-0400.

Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

July 1, 2015

Volume

75

Issue

13

Start / End Page

2699 / 2707

Location

United States

Related Subject Headings

  • Ubiquitin-Protein Ligases
  • S Phase Cell Cycle Checkpoints
  • Oncology & Carcinogenesis
  • Nuclear Proteins
  • MCF-7 Cells
  • M Phase Cell Cycle Checkpoints
  • Humans
  • Histone Chaperones
  • Hela Cells
  • HeLa Cells