Oncotarget

Research Papers:

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

Jason M. Beckta _, Seth M. Dever, Nisha Gnawali, Ashraf Khalil, Amrita Sule, Sarah E. Golding, Elizabeth Rosenberg, Aarthi Narayanan, Kylene Kehn-Hall, Bo Xu, Lawrence F. Povirk, Kristoffer Valerie

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Oncotarget. 2015; 6:27674-27687. https://doi.org/10.18632/oncotarget.4876

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This article has been corrected. Oncotarget. 2016; 7(36):58716. https://doi.org/10.18632/oncotarget.11846


Abstract

Jason M. Beckta1,2,*, Seth M. Dever1,2,*, Nisha Gnawali1, Ashraf Khalil1, Amrita Sule1,2, Sarah E. Golding1, Elizabeth Rosenberg1, Aarthi Narayanan3, Kylene Kehn-Hall3, Bo Xu4, Lawrence F. Povirk5, Kristoffer Valerie1,2,6

1Department of Radiation Oncology, Virginia Commonwealth University, Richmond, VA 23298, USA

2Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA

3National Center for Biodefense and Infectious Diseases, George Mason University, Manassas, VA 20110, USA

4Cancer Research Department, Southern Research Institute, Birmingham, AL 35205, USA

5Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA

6Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA

*These authors have contributed equally to this work

Correspondence to:

Kristoffer Valerie, e-mail: kvalerie@vcu.edu

Keywords: radiation, DNA damage, DNA repair, phosphorylation, cell cycle

Received: June 30, 2015     Accepted: July 31, 2015     Published: August 12, 2015

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.

Author Information

Jason M. Beckta
Primary Contact  _

Seth M. Dever

Nisha Gnawali

Ashraf Khalil

Amrita Sule

Sarah E. Golding

Elizabeth Rosenberg

Aarthi Narayanan

Kylene Kehn-Hall

Bo Xu

Lawrence F. Povirk

Kristoffer Valerie


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