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

Oncotarget
Jason M BecktaKristoffer Valerie

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-...Continue Reading

References

Oct 28, 1998·Proceedings of the National Academy of Sciences of the United States of America·L C Hsu, R L White
Nov 5, 1999·Molecular Cell·M E MoynahanM Jasin
Apr 21, 2001·Molecular and Cellular Biology·B XuM B Kastan
Jan 26, 2002·Molecular and Cellular Biology·Bo XuMichael B Kastan
Oct 16, 2003·Molecular and Cellular Biology·Ulrica K WestermarkMary Ellen Moynahan
Oct 25, 2003·Science·Xiaochun YuJunjie Chen
Jan 1, 2004·Molecular and Cellular Biology·Junran ZhangFen Xia
Apr 28, 2004·Current Opinion in Genetics & Development·Patrick MeraldiErich A Nigg
Jun 4, 2004·Genes & Development·Risa KitagawaMichael B Kastan
Jan 15, 2005·Proceedings of the National Academy of Sciences of the United States of America·Xingxu HuangPumin Zhang
Jun 24, 2006·Molecular Cell·Bing XiaDavid M Livingston
Jul 5, 2006·Genes & Development·Xiaochun YuJunjie Chen
Jan 30, 2007·Molecular Cancer Research : MCR·Christiana DelloRussoElizabeth M Swisher
May 26, 2007·Science·Bijan SobhianRoger A Greenberg
Jul 24, 2007·Nature Structural & Molecular Biology·Zixing LiuXiaochun Yu
Jul 24, 2007·Nature Structural & Molecular Biology·Hongtae KimJunjie Chen
Aug 1, 2007·Molecular and Cellular Biology·Easwari Kumaraswamy, Ramin Shiekhattar
Oct 30, 2007·Nature·Alessandro A SartoriStephen P Jackson
Feb 13, 2008·Cell·Asako Sakaue-SawanoAtsushi Miyawaki
Sep 23, 2008·Biochimica Et Biophysica Acta·Corinne Chabalier-TasteFlorence Larminat
Dec 18, 2008·Proceedings of the National Academy of Sciences of the United States of America·Latarsha J ReidThomas Ludwig
Feb 10, 2009·The Journal of Biological Chemistry·Pablo Huertas, Stephen P Jackson
Mar 10, 2009·Current Biology : CB·Feng ZhangXiaochun Yu
Apr 17, 2009·Proceedings of the National Academy of Sciences of the United States of America·Shirley M H SyJunjie Chen
Dec 24, 2009·Nature Reviews. Molecular Cell Biology·Michael S Y HuenJunjie Chen
Feb 24, 2010·Nature Reviews. Molecular Cell Biology·Mary Ellen Moynahan, Maria Jasin
Feb 22, 2011·The Journal of Biological Chemistry·Kara A Coleman, Roger A Greenberg
Aug 20, 2011·Molecular Oncology·Yael Aylon, Moshe Oren
Mar 29, 2014·Science·Ashok R Venkitaraman

❮ Previous
Next ❯

Citations

Jul 8, 2017·Familial Cancer·Ana KrivokucaSrdjan Novakovic
Feb 7, 2020·Journal of Controlled Release : Official Journal of the Controlled Release Society·Jasmine AllenKristoffer Valerie
Oct 1, 2021·Science·Minkyu KimNevan J Krogan

❮ Previous
Next ❯

Datasets Mentioned

BETA
EU424173.1

Methods Mentioned

BETA
ubiquitination
flow cytometry
co-immunoprecipitations
fluorescence microscopy
PCR
fluorescence-activated cell sorting
mitotic aberrations
Assay

Software Mentioned

PerkinElmer
GraphPad Prism
Volocity
GraphPad
ZEN

Related Concepts

Related Feeds

Cell Checkpoints & Regulators

Cell cycle checkpoints are a series of complex checkpoint mechanisms that detect DNA abnormalities and ensure that DNA replication and repair are complete before cell division. They are primarily regulated by cyclins, cyclin-dependent kinases, and the anaphase-promoting complex/cyclosome. Here is the latest research.

Breast Cancer: BRCA1 & BRCA2

Mutations involving BRCA1, found on chromosome 17, and BRCA2, found on chromosome 13, increase the risk for specific cancers, such as breast cancer. Discover the last research on breast cancer BRCA1 and BRCA2 here.

Ataxia telangiectasia (MDS)

Ataxia telangiectasia is a rare neurodegenerative diseases caused by defects in the ATM gene, which is involved in DNA damage recognition and repair pathways. Here is the latest research on this autosomal recessive disease.

Cell Cycle Pathways

Cell cycle is a complex process regulated by several signal transduction pathways and enzymes. Here is the latest research on regulation of cell cycle and cell cycle pathways.

Breast Cancer: Risk Factors

Breast cancer is a multifactorial disease that is influenced by both environmental and genetic factors. Discover the latest research on the environmental and genetic risk factors for breast cancer here.