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

摘要: // Jason M. Beckta 1, 2, * , Seth Dever Nisha Gnawali 1 Ashraf Khalil Amrita Sule 2 Sarah E. Golding Elizabeth Rosenberg Aarthi Narayanan 3 Kylene Kehn-Hall Bo Xu 4 Lawrence F. Povirk 5 Kristoffer Valerie 6 Department of Radiation Oncology, Virginia Commonwealth University, Richmond, VA 23298, USA Biochemistry and Molecular Biology, National Center for Biodefense Infectious Diseases, George Mason Manassas, 20110, Cancer Research Department, Southern Institute, Birmingham, AL 35205, Pharmacology Toxicology, Massey Center, These authors have contributed equally to this work Correspondence to: Valerie, e-mail: kvalerie@vcu.edu Keywords: radiation, DNA damage, repair, phosphorylation, cell cycle Received: June 30, 2015      Accepted: July 31, Published: August 12, 2015 ABSTRACT Mutations in the breast cancer susceptibility ( BRCA1 ) gene are catalysts ovarian cancers. Most mutations associated with N- C-terminal domains linked double-strand break (DSB) repair. However, little is known about role intervening serine-glutamine (SQ) - cluster damage response beyond its importance regulating checkpoints. We show that serine-to-alanine alterations at critical residues within SQ-cluster be phosphorylated by ATM ATR result reduced homologous recombination repair (HRR) aberrant mitosis. While a S1387A mutant previously shown abrogate S-phase arrest radiation resulted only modest decrease HRR, together an additional alteration, S1423A (BRCA1 2P ), HRR vector control levels similar quadruple also including S1457A S1524A 4P ). effects appeared independent PALB2. Furthermore, we found promoted prolonged struggling late shifted DSB from non-homologous end joining which, face irreparable chromosomal mitotic catastrophe. Altogether, phosphorylation allowing adequate time completing normal prior mitosis preventing cells entering G1 prematurely resulting gross aberrations.