Structure of BRCA1-BRCT/Abraxas Complex Reveals Phosphorylation-Dependent BRCT Dimerization at DNA Damage Sites.

Molecular Cell
Qian WuTom L Blundell

Abstract

BRCA1 accumulation at DNA damage sites is an important step for its function in the DNA damage response and in DNA repair. BRCA1-BRCT domains bind to proteins containing the phosphorylated serine-proline-x-phenylalanine (pSPxF) motif including Abraxas, Bach1/FancJ, and CtIP. In this study, we demonstrate that ionizing radiation (IR)-induces ATM-dependent phosphorylation of serine 404 (S404) next to the pSPxF motif. Crystal structures of BRCT/Abraxas show that phosphorylation of S404 is important for extensive interactions through the N-terminal sequence outside the pSPxF motif and leads to formation of a stable dimer. Mutation of S404 leads to deficiency in BRCA1 accumulation at DNA damage sites and cellular sensitivity to IR. In addition, two germline mutations of BRCA1 are found to disrupt the dimer interface and dimer formation. Thus, we demonstrate a mechanism involving IR-induced phosphorylation and dimerization of the BRCT/Abraxas complex for regulating Abraxas-mediated recruitment of BRCA1 in response to IR.

References

Oct 7, 1994·Science·P A FutrealY Miki
Nov 13, 2002·The Journal of Biological Chemistry·R Scott Williams, J N Mark Glover
Oct 9, 2003·The EMBO Journal·Tamar UzielYosef Shiloh
Oct 25, 2003·Science·Isaac A MankeMichael B Yaffe
Oct 25, 2003·Science·Xiaochun YuJunjie Chen
Oct 28, 2003·The Journal of Biological Chemistry·Maria RodriguezZhou Songyang
May 11, 2004·Nature Structural & Molecular Biology·Julie A ClappertonStephen J Smerdon
May 11, 2004·Nature Structural & Molecular Biology·R Scott WilliamsJ N Mark Glover
Oct 27, 2004·Trends in Biochemical Sciences·J N Mark GloverMegan S Lee
Aug 17, 2005·Biochemistry·Ashok K VarmaJohn A A Ladias
Apr 5, 2007·Nature Protocols·Helena Hernández, Carol V Robinson
Jul 24, 2007·Nature Structural & Molecular Biology·Zixing LiuXiaochun Yu
Jul 24, 2007·Nature Structural & Molecular Biology·Hongtae KimJunjie Chen
Nov 17, 2007·Science·Nadine K KolasDaniel Durocher
Dec 14, 2007·Proceedings of the National Academy of Sciences of the United States of America·Bin Wang, Stephen J Elledge
Dec 18, 2007·Molecular Cell·J Wade Harper, Stephen J Elledge
Dec 19, 2007·Cell Research·Michael S Y Huen, Junjie Chen
Nov 19, 2008·Molecular and Cellular Biology·Jiaxue WuXiaochun Yu
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Wolfgang Kabsch
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Paul D AdamsPeter H Zwart
Apr 9, 2011·Biochemistry·Nicolas CoquelleJ N Mark Glover
Jul 8, 2011·Cell Cycle·Charles Chung Yun Leung, J N Mark Glover
Oct 1, 2013·Biochemistry·Xuying Liu, John A A Ladias
Feb 24, 2015·Progress in Biophysics and Molecular Biology·Qian WuTom L Blundell

❮ Previous
Next ❯

Citations

Dec 24, 2016·Cell Reports·Otto J P KyrieleisStephen J Smerdon
Mar 10, 2017·European Journal of Cancer Prevention : the Official Journal of the European Cancer Prevention Organisation (ECP)·Giovanni CorsoViviana Galimberti
Feb 24, 2018·Biochemical Society Transactions·Miriam WaldenElton Zeqiraj
Aug 26, 2019·Molecular and Cellular Biochemistry·Maurilio da Silva MorroneJosé Cláudio Fonseca Moreira
Jun 12, 2016·The Journal of Biological Chemistry·Hoi-Man NgMichael S Y Huen
Apr 27, 2019·Scientific Reports·Steven E GuardWilliam M Old
Dec 13, 2019·Nature Communications·Yifan WangNeil Johnson
Jul 12, 2020·Molecular & Cellular Proteomics : MCP·Svenja WiechmannSophie Dobiasch
Mar 10, 2017·Cell Cycle·Thales C NepomucenoMarcelo A Carvalho
Nov 22, 2019·Cellular and Molecular Life Sciences : CMLS·Yueru SunXiaodong Zhang
Mar 20, 2020·Cell & Bioscience·Wenjun LiuYanbin Zhang
May 2, 2020·Signal Transduction and Targeted Therapy·Rui-Xue Huang, Ping-Kun Zhou
Jun 15, 2018·Nature·Moritz HunkelerTimm Maier
Sep 28, 2018·Molecular Cancer Research : MCR·Ambre PetitalotUNKNOWN UNICANCER Genetic Group BRCA network
Apr 8, 2020·Computational and Structural Biotechnology Journal·Siddharth Sinha, San Ming Wang
Jan 14, 2021·The Biochemical Journal·Rashmi Panigrahi, J N Mark Glover
Jan 3, 2021·Journal of Molecular Biology·Kirill E MedvedevNick V Grishin
Aug 1, 2020·Cancer Research·Dongju ParkThomas Ludwig
Jan 17, 2021·Molecular & Cellular Proteomics : MCP·Svenja WiechmannSophie Dobiasch
Jun 30, 2019·Molecular Cell·Julius RablNicolas H Thomä
Dec 2, 2020·Progress in Biophysics and Molecular Biology·Rhys M Williams, Xiaodong Zhang
Sep 29, 2020·DNA Repair·Ahhyun KimW Matthew Michael
Apr 23, 2021·Progress in Biophysics and Molecular Biology·Rhys M Williams, Xiaodong Zhang
Oct 1, 2021·Science·Minkyu KimNevan J Krogan
Feb 18, 2018·Current Problems in Cancer·Babita SharmaAnjana Munshi

❮ Previous
Next ❯

Methods Mentioned

BETA
chromosomal aberration
size exclusion chromatography
gel filtration
X-ray
co-immunoprecipitation
Myc-immunoprecipitation
immunoprecipitation
ubiquitination

Software Mentioned

Scala
Phenix
XDS

Related Concepts

Related Feeds

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.

Ataxia telangiectasia

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.

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.