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Oncotarget. 2015 Sep 29;6(29):27674-87. doi: 10.18632/oncotarget.4876.

Mutation of the BRCA1 SQ-cluster results in aberrant mitosis, reduced homologous recombination, and a compensatory increase in non-homologous end joining.

Author information

1
Department of Radiation Oncology, Virginia Commonwealth University, Richmond, VA 23298, USA.
2
Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA.
3
National Center for Biodefense and Infectious Diseases, George Mason University, Manassas, VA 20110, USA.
4
Cancer Research Department, Southern Research Institute, Birmingham, AL 35205, USA.
5
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA.
6
Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.

Abstract

Mutations in the breast cancer susceptibility 1 (BRCA1) gene are catalysts for breast and ovarian cancers. Most mutations are associated with the BRCA1 N- and C-terminal domains linked to DNA double-strand break (DSB) repair. However, little is known about the role of the intervening serine-glutamine (SQ) - cluster in the DNA damage response beyond its importance in regulating cell cycle checkpoints. We show that serine-to-alanine alterations at critical residues within the SQ-cluster known to be phosphorylated by ATM and ATR result in reduced homologous recombination repair (HRR) and aberrant mitosis. While a S1387A BRCA1 mutant - previously shown to abrogate S-phase arrest in response to radiation - resulted in only a modest decrease in HRR, S1387A together with an additional alteration, S1423A (BRCA12P), reduced HRR to vector control levels and similar to a quadruple mutant also including S1457A and S1524A (BRCA14P). These effects appeared to be independent of PALB2. Furthermore, we found that BRCA14P promoted a prolonged and struggling HRR late in the cell cycle and shifted DSB repair from HRR to non-homologous end joining which, in the face of irreparable chromosomal damage, resulted in mitotic catastrophe. Altogether, SQ-cluster phosphorylation is critical for allowing adequate time for completing normal HRR prior to mitosis and preventing cells from entering G1 prematurely resulting in gross chromosomal aberrations.

KEYWORDS:

DNA damage; DNA repair; cell cycle; phosphorylation; radiation

PMID:
26320175
PMCID:
PMC4695017
DOI:
10.18632/oncotarget.4876
[Indexed for MEDLINE]
Free PMC Article

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