Home LiteratureArticle Details
PMID: 19261748 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

MERIT40 facilitates BRCA1 localization and DNA damage repair.

Genes & development ·Vol. 23 ·No. 6 ·2009-03-15 ·Pages 719-28

Feng L, Huang J, Chen J

Abstract

The product of breast cancer susceptibility gene 1, BRCA1, plays pivotal roles in the maintenance of genomic integrity. Mounting evidence indicates that BRCA1 associates with many proteins or protein complexes to regulate diverse processes important for the cellular response to DNA damage. One of these complexes, which mediates the accumulation of BRCA1 at sites of DNA breaks, involves the ubiquitin-binding motif (UIM)-containing protein RAP80, a coiled-coil domain protein CCDC98/Abraxas, and a deubiquitinating enzyme BRCC36. Here we describe the characterization of a novel component of this complex, MERIT40 (Mediator of Rap80 Interactions and Targeting 40 kd), which together with an adaptor protein BRE/BRCC45, enforces the BRCA1-dependent DNA damage response. MERIT40 is assembled into this RAP80/CCDC98-containing complex via its direct interaction with BRE/BRCC45. Importantly, MERIT40 regulates BRCA1 retention at DNA breaks and checkpoint function primarily via a role in maintaining the stability of BRE and this five-subunit protein complex at sites of DNA damage. Together, our study reveals that a stable complex containing MERIT40 acts early in DNA damage response and regulates damage-dependent BRCA1 localization.

MeSH Terms
Adaptor Proteins, Signal Transducing BRCA1 Protein/metabolism,physiology Carrier Proteins/metabolism Cell Line, Tumor DNA Damage/physiology DNA Repair/physiology DNA-Binding Proteins Deubiquitinating Enzymes Histone Chaperones Humans Membrane Proteins/metabolism Multiprotein Complexes/physiology Nerve Tissue Proteins/metabolism Nuclear Proteins/metabolism
Chemicals
ABRAXAS1 protein, human Adaptor Proteins, Signal Transducing BABAM1 protein, human BABAM2 protein, human BRCA1 Protein Carrier Proteins DNA-Binding Proteins Histone Chaperones Membrane Proteins Multiprotein Complexes Nerve Tissue Proteins Nuclear Proteins UIMC1 protein, human BRCC3 protein, human Deubiquitinating Enzymes
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Feng Lin
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Huang Jun
Chen Junjie
References (39)
39 references, click to expand
  1. The BRCT domain is a phospho-protein binding domain.
    Science. 2003 Oct 24;302(5645):639-42 PMID: 14576433
  2. RING finger proteins: mediators of ubiquitin ligase activity.
    Cell. 2000 Sep 1;102(5):549-52 PMID: 11007473
  3. RAP80 targets BRCA1 to specific ubiquitin structures at DNA damage sites.
    Science. 2007 May 25;316(5828):1198-202 PMID: 17525341
  4. De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling.
    Nature. 2004 Aug 5;430(7000):694-9 PMID: 15258597
  5. A conserved pathway to activate BRCA1-dependent ubiquitylation at DNA damage sites.
    EMBO J. 2006 May 17;25(10):2178-88 PMID: 16628214
  6. Orchestration of the DNA-damage response by the RNF8 ubiquitin ligase.
    Science. 2007 Dec 7;318(5856):1637-40 PMID: 18006705
  7. OTU takes the chains OUT.
    Nat Chem Biol. 2008 Apr;4(4):227-8 PMID: 18347589
  8. Abraxas and RAP80 form a BRCA1 protein complex required for the DNA damage response.
    Science. 2007 May 25;316(5828):1194-8 PMID: 17525340
  9. Large-scale mapping of human protein-protein interactions by mass spectrometry.
    Mol Syst Biol. 2007;3:89 PMID: 17353931
  10. Binding of CtIP to the BRCT repeats of BRCA1 involved in the transcription regulation of p21 is disrupted upon DNA damage.
    J Biol Chem. 1999 Apr 16;274(16):11334-8 PMID: 10196224
  11. A critical role for histone H2AX in recruitment of repair factors to nuclear foci after DNA damage.
    Curr Biol. 2000 Jul 27-Aug 10;10(15):886-95 PMID: 10959836
  12. Dynamic changes of BRCA1 subnuclear location and phosphorylation state are initiated by DNA damage.
    Cell. 1997 Aug 8;90(3):425-35 PMID: 9267023
  13. BRCA1 : BARD1 induces the formation of conjugated ubiquitin structures, dependent on K6 of ubiquitin, in cells during DNA replication and repair.
    Hum Mol Genet. 2004 Apr 15;13(8):807-17 PMID: 14976165
  14. Identification of a brain- and reproductive-organs-specific gene responsive to DNA damage and retinoic acid.
    Biochem Biophys Res Commun. 1995 Jan 17;206(2):764-74 PMID: 7826398
  15. BRCC36 is essential for ionizing radiation-induced BRCA1 phosphorylation and nuclear foci formation.
    Cancer Res. 2006 May 15;66(10):5039-46 PMID: 16707425
  16. RNF8 transduces the DNA-damage signal via histone ubiquitylation and checkpoint protein assembly.
    Cell. 2007 Nov 30;131(5):901-14 PMID: 18001825
  17. CCDC98 targets BRCA1 to DNA damage sites.
    Nat Struct Mol Biol. 2007 Aug;14(8):716-20 PMID: 17643121
  18. CCDC98 is a BRCA1-BRCT domain-binding protein involved in the DNA damage response.
    Nat Struct Mol Biol. 2007 Aug;14(8):710-5 PMID: 17643122
  19. BRCA1-mediated ubiquitylation.
    Cell Cycle. 2006 Jul;5(14):1481-6 PMID: 16861894
  20. Histone H2AX phosphorylation is dispensable for the initial recognition of DNA breaks.
    Nat Cell Biol. 2003 Jul;5(7):675-9 PMID: 12792649
  21. BRCA1 ubiquitinates its phosphorylation-dependent binding partner CtIP.
    Genes Dev. 2006 Jul 1;20(13):1721-6 PMID: 16818604
  22. BACH1, a novel helicase-like protein, interacts directly with BRCA1 and contributes to its DNA repair function.
    Cell. 2001 Apr 6;105(1):149-60 PMID: 11301010
  23. RNF8 ubiquitylates histones at DNA double-strand breaks and promotes assembly of repair proteins.
    Cell. 2007 Nov 30;131(5):887-900 PMID: 18001824
  24. RAP80 and RNF8, key players in the recruitment of repair proteins to DNA damage sites.
    Cancer Lett. 2008 Nov 28;271(2):179-90 PMID: 18550271
  25. Ubiquitin-binding protein RAP80 mediates BRCA1-dependent DNA damage response.
    Science. 2007 May 25;316(5828):1202-5 PMID: 17525342
  26. The BRCA1/BARD1 heterodimer, a tumor suppressor complex with ubiquitin E3 ligase activity.
    Curr Opin Genet Dev. 2002 Feb;12(1):86-91 PMID: 11790560
  27. Ubc13/Rnf8 ubiquitin ligases control foci formation of the Rap80/Abraxas/Brca1/Brcc36 complex in response to DNA damage.
    Proc Natl Acad Sci U S A. 2007 Dec 26;104(52):20759-63 PMID: 18077395
  28. Linking the cellular functions of BRCA genes to cancer pathogenesis and treatment.
    Annu Rev Pathol. 2009;4:461-87 PMID: 18954285
  29. The C-terminal (BRCT) domains of BRCA1 interact in vivo with CtIP, a protein implicated in the CtBP pathway of transcriptional repression.
    J Biol Chem. 1998 Sep 25;273(39):25388-92 PMID: 9738006
  30. A critical role for the ubiquitin-conjugating enzyme Ubc13 in initiating homologous recombination.
    Mol Cell. 2007 Mar 9;25(5):663-75 PMID: 17349954
  31. Regulation of BRCC, a holoenzyme complex containing BRCA1 and BRCA2, by a signalosome-like subunit and its role in DNA repair.
    Mol Cell. 2003 Nov;12(5):1087-99 PMID: 14636569
  32. Recognition of DNA double strand breaks by the BRCA1 tumor suppressor network.
    Chromosoma. 2008 Aug;117(4):305-17 PMID: 18369654
  33. The role of BRCA1 in transcriptional regulation and cell cycle control.
    Oncogene. 2006 Sep 25;25(43):5854-63 PMID: 16998500
  34. Towards a proteome-scale map of the human protein-protein interaction network.
    Nature. 2005 Oct 20;437(7062):1173-8 PMID: 16189514
  35. BRCT repeats as phosphopeptide-binding modules involved in protein targeting.
    Science. 2003 Oct 24;302(5645):636-9 PMID: 14576432
  36. DNA damage: ubiquitin marks the spot.
    Nat Struct Mol Biol. 2008 Jan;15(1):20-2 PMID: 18176551
  37. The RING heterodimer BRCA1-BARD1 is a ubiquitin ligase inactivated by a breast cancer-derived mutation.
    J Biol Chem. 2001 May 4;276(18):14537-40 PMID: 11278247
  38. Multifactorial contributions to an acute DNA damage response by BRCA1/BARD1-containing complexes.
    Genes Dev. 2006 Jan 1;20(1):34-46 PMID: 16391231
  39. DNA damage-induced cell cycle checkpoint control requires CtIP, a phosphorylation-dependent binding partner of BRCA1 C-terminal domains.
    Mol Cell Biol. 2004 Nov;24(21):9478-86 PMID: 15485915
Article Info
Journal
Genes & development
Abbr.
Genes Dev
ISSN
1549-5477
DOI
10.1101/gad.1770609
Published
2009-03-15
Epub
2009-00-04
Pages
719-28
Language
English
Region
United States
NLM ID
8711660
PMCID
PMC2661609
Subset
IM
Grants
NCI NIH HHS · R01 CA089239-09 · United States
NCI NIH HHS · R01 CA092312 · United States
NCI NIH HHS · R01 CA089239 · United States
NCI NIH HHS · CA092312 · United States
NCI NIH HHS · R01 CA092312-09 · United States
NCI NIH HHS · CA089239 · United States
External Links
PubMed source DOI: 10.1101/gad.1770609 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2