Home LiteratureArticle Details
PMID: 23306439 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't

Rif1 prevents resection of DNA breaks and promotes immunoglobulin class switching.

Science (New York, N.Y.) ·Vol. 339 ·No. 6120 ·2013-02-08 ·Pages 711-5

Di Virgilio M, Callen E, Yamane A, Zhang W, Jankovic M, Gitlin AD, Feldhahn N, Resch W, Oliveira TY, Chait BT, Nussenzweig A, Casellas R, Robbiani DF, Nussenzweig MC

Abstract

DNA double-strand breaks (DSBs) represent a threat to the genome because they can lead to the loss of genetic information and chromosome rearrangements. The DNA repair protein p53 binding protein 1 (53BP1) protects the genome by limiting nucleolytic processing of DSBs by a mechanism that requires its phosphorylation, but whether 53BP1 does so directly is not known. Here, we identify Rap1-interacting factor 1 (Rif1) as an ATM (ataxia-telangiectasia mutated) phosphorylation-dependent interactor of 53BP1 and show that absence of Rif1 results in 5'-3' DNA-end resection in mice. Consistent with enhanced DNA resection, Rif1 deficiency impairs DNA repair in the G(1) and S phases of the cell cycle, interferes with class switch recombination in B lymphocytes, and leads to accumulation of chromosome DSBs.

MeSH Terms
Animals Ataxia Telangiectasia Mutated Proteins B-Lymphocytes/immunology,metabolism Cell Cycle Proteins/antagonists & inhibitors,metabolism Cells, Cultured Chromosomal Proteins, Non-Histone/metabolism DNA/metabolism DNA Breaks, Double-Stranded DNA Repair DNA-Binding Proteins/antagonists & inhibitors,metabolism G1 Phase G2 Phase Genomic Instability Immunoglobulin Class Switching Mice Phosphorylation Protein Serine-Threonine Kinases/antagonists & inhibitors,metabolism S Phase Telomere-Binding Proteins/metabolism Tumor Suppressor Proteins/antagonists & inhibitors,metabolism Tumor Suppressor p53-Binding Protein 1
Chemicals
Cell Cycle Proteins Chromosomal Proteins, Non-Histone DNA-Binding Proteins Rif1 protein, mouse Telomere-Binding Proteins Trp53bp1 protein, mouse Tumor Suppressor Proteins Tumor Suppressor p53-Binding Protein 1 DNA Ataxia Telangiectasia Mutated Proteins Atm protein, mouse Protein Serine-Threonine Kinases
Authors & Affiliations
14 authors, click to expand affiliations / ORCID
Di Virgilio Michela
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
Callen Elsa
Yamane Arito
Zhang Wenzhu
Jankovic Mila
Gitlin Alexander D
Feldhahn Niklas
Resch Wolfgang
Oliveira Thiago Y
Chait Brian T
Nussenzweig André
Casellas Rafael
Robbiani Davide F
Nussenzweig Michel C
References (48)
48 references, click to expand
  1. Double-strand break end resection and repair pathway choice.
    Annu Rev Genet. 2011;45:247-71 PMID: 21910633
  2. H2AX is required for recombination between immunoglobulin switch regions but not for intra-switch region recombination or somatic hypermutation.
    J Exp Med. 2003 Jun 16;197(12):1767-78 PMID: 12810694
  3. ATM prevents the persistence and propagation of chromosome breaks in lymphocytes.
    Cell. 2007 Jul 13;130(1):63-75 PMID: 17599403
  4. AID targeting in antibody diversity.
    Adv Immunol. 2011;110:1-26 PMID: 21762814
  5. RPA accumulation during class switch recombination represents 5'-3' DNA-end resection during the S-G2/M phase of the cell cycle.
    Cell Rep. 2013 Jan 31;3(1):138-47 PMID: 23291097
  6. Somatic hypermutation is limited by CRM1-dependent nuclear export of activation-induced deaminase.
    J Exp Med. 2004 May 3;199(9):1235-44 PMID: 15117971
  7. MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification.
    Nat Biotechnol. 2008 Dec;26(12):1367-72 PMID: 19029910
  8. Tying the loose ends together in DNA double strand break repair with 53BP1.
    Cell Div. 2006 Aug 31;1:19 PMID: 16945145
  9. B lymphocyte-specific, Cre-mediated mutagenesis in mice.
    Nucleic Acids Res. 1997 Mar 15;25(6):1317-8 PMID: 9092650
  10. Essential role for DNA-PKcs in DNA double-strand break repair and apoptosis in ATM-deficient lymphocytes.
    Mol Cell. 2009 May 15;34(3):285-97 PMID: 19450527
  11. Enhanced intra-switch region recombination during immunoglobulin class switch recombination in 53BP1-/- B cells.
    Eur J Immunol. 2007 Jan;37(1):235-9 PMID: 17183606
  12. BRCT repeats as phosphopeptide-binding modules involved in protein targeting.
    Science. 2003 Oct 24;302(5645):636-9 PMID: 14576432
  13. A RAP1-interacting protein involved in transcriptional silencing and telomere length regulation.
    Genes Dev. 1992 May;6(5):801-14 PMID: 1577274
  14. Human Rif1 protein binds aberrant telomeres and aligns along anaphase midzone microtubules.
    J Cell Biol. 2004 Dec 6;167(5):819-30 PMID: 15583028
  15. AID is required to initiate Nbs1/gamma-H2AX focus formation and mutations at sites of class switching.
    Nature. 2001 Dec 6;414(6864):660-665 PMID: 11740565
  16. The GAR motif of 53BP1 is arginine methylated by PRMT1 and is necessary for 53BP1 DNA binding activity.
    Cell Cycle. 2005 Dec;4(12):1834-41 PMID: 16294045
  17. 53BP1 links DNA damage-response pathways to immunoglobulin heavy chain class-switch recombination.
    Nat Immunol. 2004 May;5(5):481-7 PMID: 15077110
  18. Regulation of DNA end joining, resection, and immunoglobulin class switch recombination by 53BP1.
    Mol Cell. 2011 May 6;42(3):319-29 PMID: 21549309
  19. 53BP1-mediated DNA double strand break repair: insert bad pun here.
    DNA Repair (Amst). 2011 Oct 10;10(10):1071-6 PMID: 21868291
  20. Human CtIP promotes DNA end resection.
    Nature. 2007 Nov 22;450(7169):509-14 PMID: 17965729
  21. Regulation of chromatin architecture by the PWWP domain-containing DNA damage-responsive factor EXPAND1/MUM1.
    Mol Cell. 2010 Mar 26;37(6):854-64 PMID: 20347427
  22. 53BP1 regulates DNA resection and the choice between classical and alternative end joining during class switch recombination.
    J Exp Med. 2010 Apr 12;207(4):855-65 PMID: 20368578
  23. Rif1 provides a new DNA-binding interface for the Bloom syndrome complex to maintain normal replication.
    EMBO J. 2010 Sep 15;29(18):3140-55 PMID: 20711169
  24. 53BP1 is required for class switch recombination.
    J Cell Biol. 2004 May 24;165(4):459-64 PMID: 15159415
  25. Rif1 regulates the replication timing domains on the human genome.
    EMBO J. 2012 Sep 12;31(18):3667-77 PMID: 22850674
  26. AID is required for the chromosomal breaks in c-myc that lead to c-myc/IgH translocations.
    Cell. 2008 Dec 12;135(6):1028-38 PMID: 19070574
  27. Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme.
    Cell. 2000 Sep 1;102(5):553-63 PMID: 11007474
  28. 53BP1-dependent robust localized KAP-1 phosphorylation is essential for heterochromatic DNA double-strand break repair.
    Nat Cell Biol. 2010 Feb;12(2):177-84 PMID: 20081839
  29. Deep-sequencing identification of the genomic targets of the cytidine deaminase AID and its cofactor RPA in B lymphocytes.
    Nat Immunol. 2011 Jan;12(1):62-9 PMID: 21113164
  30. DNA damage defines sites of recurrent chromosomal translocations in B lymphocytes.
    Nature. 2012 Feb 07;484(7392):69-74 PMID: 22314321
  31. The 8-kDa dynein light chain binds to p53-binding protein 1 and mediates DNA damage-induced p53 nuclear accumulation.
    J Biol Chem. 2005 Mar 4;280(9):8172-9 PMID: 15611139
  32. A DNA damage-regulated BRCT-containing protein, TopBP1, is required for cell survival.
    Mol Cell Biol. 2002 Jan;22(2):555-66 PMID: 11756551
  33. Complete rescue of obesity, diabetes, and infertility in db/db mice by neuron-specific LEPR-B transgenes.
    J Clin Invest. 2005 Dec;115(12):3484-93 PMID: 16284652
  34. Automatic identification of proteins with a MALDI-quadrupole ion trap mass spectrometer.
    Anal Chem. 2001 Nov 1;73(21):5066-77 PMID: 11721901
  35. More than just a focus: The chromatin response to DNA damage and its role in genome integrity maintenance.
    Nat Cell Biol. 2011 Oct 03;13(10):1161-9 PMID: 21968989
  36. Protocol for micro-purification, enrichment, pre-fractionation and storage of peptides for proteomics using StageTips.
    Nat Protoc. 2007;2(8):1896-906 PMID: 17703201
  37. Mouse Rif1 is a key regulator of the replication-timing programme in mammalian cells.
    EMBO J. 2012 Sep 12;31(18):3678-90 PMID: 22850673
  38. 53BP1 facilitates long-range DNA end-joining during V(D)J recombination.
    Nature. 2008 Nov 27;456(7221):529-33 PMID: 18931658
  39. Role for Rif1 in the checkpoint response to damaged DNA in Xenopus egg extracts.
    Cell Cycle. 2012 Mar 15;11(6):1183-94 PMID: 22391207
  40. Tumor suppressor p53 binding protein 1 (53BP1) is involved in DNA damage-signaling pathways.
    J Cell Biol. 2001 Apr 30;153(3):613-20 PMID: 11331310
  41. 53BP1 promotes non-homologous end joining of telomeres by increasing chromatin mobility.
    Nature. 2008 Nov 27;456(7221):524-8 PMID: 18931659
  42. Role of genomic instability and p53 in AID-induced c-myc-Igh translocations.
    Nature. 2006 Mar 2;440(7080):105-9 PMID: 16400328
  43. Rif1 is a global regulator of timing of replication origin firing in fission yeast.
    Genes Dev. 2012 Jan 15;26(2):137-50 PMID: 22279046
  44. Mammalian Rif1 contributes to replication stress survival and homology-directed repair.
    J Cell Biol. 2009 Nov 2;187(3):385-98 PMID: 19948482
  45. Activation-induced cytidine deaminase targets DNA at sites of RNA polymerase II stalling by interaction with Spt5.
    Cell. 2010 Oct 1;143(1):122-33 PMID: 20887897
  46. Genome-wide analysis of transcription factor binding sites based on ChIP-Seq data.
    Nat Methods. 2008 Sep;5(9):829-34 PMID: 19160518
  47. Host factors associated with the Sindbis virus RNA-dependent RNA polymerase: role for G3BP1 and G3BP2 in virus replication.
    J Virol. 2010 Jul;84(13):6720-32 PMID: 20392851
  48. Human Rif1, ortholog of a yeast telomeric protein, is regulated by ATM and 53BP1 and functions in the S-phase checkpoint.
    Genes Dev. 2004 Sep 1;18(17):2108-19 PMID: 15342490
Article Info
Journal
Science (New York, N.Y.)
Abbr.
Science
ISSN
1095-9203
DOI
10.1126/science.1230624
Published
2013-02-08
Epub
2013-00-10
Pages
711-5
Language
English
Region
United States
NLM ID
0404511
PMCID
PMC3815530
Subset
IM
Grants
NIAID NIH HHS · R01 AI037526 · United States
NCRR NIH HHS · RR022220 · United States
NCRR NIH HHS · P41 RR000862 · United States
NCRR NIH HHS · U54 RR022220 · United States
NIGMS NIH HHS · GM103314 · United States
Intramural NIH HHS · United States
NIGMS NIH HHS · GM007739 · United States
NCRR NIH HHS · RR00862 · United States
NIGMS NIH HHS · T32 GM007739 · United States
Howard Hughes Medical Institute · United States
NIGMS NIH HHS · P41 GM103314 · United States
NIAID NIH HHS · AI037526 · United States
NIAID NIH HHS · R37 AI037526 · United States
Databases
GEO
GSE42298
Corrections
CommentIn
PMID: 23393250
External Links
PubMed source DOI: 10.1126/science.1230624 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