RIF1 Is Essential for 53BP1-Dependent Nonhomologous End Joining and Suppression of DNA Double-Strand Break Resection

Summary The appropriate execution of DNA double-strand break (DSB) repair is critical for genome stability and tumor avoidance. 53BP1 and BRCA1 directly influence DSB repair pathway choice by regulating 5′ end resection, but how this is achieved remains uncertain. Here we report that Rif1−/− mice are severely compromised for 53BP1-dependent class switch recombination (CSR) and fusion of dysfunctional telomeres. The inappropriate accumulation of RIF1 at DSBs in S phase is antagonized by BRCA1, and deletion of Rif1 suppresses toxic nonhomologous end joining (NHEJ) induced by PARP inhibition in Brca1-deficient cells. Mechanistically, RIF1 is recruited to DSBs via the N-terminal phospho-SQ/TQ domain of 53BP1, and DSBs generated by ionizing radiation or during CSR are hyperresected in the absence of RIF1. Thus, RIF1 and 53BP1 cooperate to block DSB resection to promote NHEJ in G1, which is antagonized by BRCA1 in S phase to ensure a switch of DSB repair mode to homologous recombination.

[1]  Reuben S Harris,et al.  Immunity through DNA deamination. , 2003, Trends in biochemical sciences.

[2]  Tom J. Petty,et al.  Methylated lysine 79 of histone H3 targets 53BP1 to DNA double-strand breaks , 2004, Nature.

[3]  A. Shibata,et al.  53BP1-dependent robust localized KAP-1 phosphorylation is essential for heterochromatic DNA double-strand break repair , 2010, Nature Cell Biology.

[4]  P. Mckinnon.  DNA repair deficiency and neurological disease , 2009, Nature Reviews Neuroscience.

[5]  S. Jackson,et al.  BRCA1-associated exclusion of 53BP1 from DNA damage sites underlies temporal control of DNA repair , 2012, Journal of Cell Science.

[6]  Yves Pommier,et al.  Rif1 provides a new DNA‐binding interface for the Bloom syndrome complex to maintain normal replication , 2010, The EMBO journal.

[7]  M. Nussenzweig,et al.  Enhanced intra‐switch region recombination during immunoglobulin class switch recombination in 53BP1–/– B cells , 2007, European journal of immunology.

[8]  Frank Eisenhaber,et al.  Human Rif1, ortholog of a yeast telomeric protein, is regulated by ATM and 53BP1 and functions in the S-phase checkpoint. , 2004, Genes & development.

[9]  M. Nussenzweig,et al.  53BP1 regulates DNA resection and the choice between classical and alternative end joining during class switch recombination , 2010, The Journal of experimental medicine.

[10]  D. Shore,et al.  A RAP1-interacting protein involved in transcriptional silencing and telomere length regulation. , 1992, Genes & development.

[11]  Georges Mer,et al.  Structural Basis for the Methylation State-Specific Recognition of Histone H4-K20 by 53BP1 and Crb2 in DNA Repair , 2006, Cell.

[12]  S. Boulton,et al.  The choice in meiosis – defining the factors that influence crossover or non-crossover formation , 2011, Journal of Cell Science.

[13]  Thomas Helleday,et al.  Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase , 2005, Nature.

[14]  S. Boulton,et al.  Playing the end game: DNA double-strand break repair pathway choice. , 2012, Molecular cell.

[15]  D. Ferguson,et al.  Mammalian Rif1 contributes to replication stress survival and homology-directed repair , 2009, The Journal of cell biology.

[16]  S Povey,et al.  Dynamic molecular combing: stretching the whole human genome for high-resolution studies. , 1997, Science.

[17]  S. West,et al.  Aberrant chromosome morphology in human cells defective for Holliday junction resolution , 2011, Nature.

[18]  W. Goedecke,et al.  Mechanisms of DNA double-strand break repair and their potential to induce chromosomal aberrations. , 2000, Mutagenesis.

[19]  T. de Lange,et al.  Shelterin: the protein complex that shapes and safeguards human telomeres. , 2005, Genes & development.

[20]  D. Adams,et al.  53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers , 2010, Nature Structural &Molecular Biology.

[21]  S. Jackson,et al.  Phospho-dependent interactions between NBS1 and MDC1 mediate chromatin retention of the MRN complex at sites of DNA damage , 2008, EMBO reports.

[22]  Bas van Steensel,et al.  TRF2 Protects Human Telomeres from End-to-End Fusions , 1998, Cell.

[23]  D. Shore,et al.  A novel Rap1p-interacting factor, Rif2p, cooperates with Rif1p to regulate telomere length in Saccharomyces cerevisiae. , 1997, Genes & development.

[24]  J. Rouse,et al.  Phospho-epitope binding by the BRCT domains of hPTIP controls multiple aspects of the cellular response to DNA damage , 2007, Nucleic acids research.

[25]  Ty C. Voss,et al.  DNA damage defines sites of recurrent chromosomal translocations in B lymphocytes , 2012, Nature.

[26]  A. Multani,et al.  The function of classical and alternative non‐homologous end‐joining pathways in the fusion of dysfunctional telomeres , 2010, The EMBO journal.

[27]  E. Nam,et al.  ATR signalling: more than meeting at the fork. , 2011, The Biochemical journal.

[28]  K. Cimprich,et al.  The structural determinants of checkpoint activation. , 2007, Genes & development.

[29]  C. E. Schrader,et al.  Mechanism and regulation of class switch recombination. , 2008, Annual review of immunology.

[30]  Michael M. Murphy,et al.  IgH class switching and translocations use a robust non-classical end-joining pathway , 2007, Nature.

[31]  M. Nussenzweig,et al.  53BP1 is required for class switch recombination , 2004, The Journal of cell biology.

[32]  Jeremy M. Stark,et al.  Alternative-NHEJ Is a Mechanistically Distinct Pathway of Mammalian Chromosome Break Repair , 2008, PLoS genetics.

[33]  Jeremy M. Stark,et al.  53BP1 Inhibits Homologous Recombination in Brca1-Deficient Cells by Blocking Resection of DNA Breaks , 2010, Cell.

[34]  M. Jasin,et al.  Human Genome and Diseases:¶Double-strand breaks and translocations in cancer , 2002, Cellular and Molecular Life Sciences CMLS.

[35]  M. Nussenzweig,et al.  Regulation of DNA end joining, resection, and immunoglobulin class switch recombination by 53BP1. , 2011, Molecular cell.

[36]  Yun Yen,et al.  Human RIF1 encodes an anti-apoptotic factor required for DNA repair. , 2009, Carcinogenesis.

[37]  C. Deng,et al.  A selective requirement for 53BP1 in the biological response to genomic instability induced by Brca1 deficiency. , 2009, Molecular cell.

[38]  Y. Taniguchi,et al.  Genetic dissection of vertebrate 53BP1: a major role in non-homologous end joining of DNA double strand breaks. , 2006, DNA repair.

[39]  D. Spector,et al.  53BP1 promotes non-homologous end joining of telomeres by increasing chromatin mobility , 2008, Nature.

[40]  Thomas Helleday,et al.  The underlying mechanism for the PARP and BRCA synthetic lethality: Clearing up the misunderstandings , 2011, Molecular oncology.

[41]  Hisao Masai,et al.  Rif1 regulates the replication timing domains on the human genome , 2012, The EMBO journal.

[42]  S. Takeda,et al.  Reverse genetic studies of the DNA damage response in the chicken B lymphocyte line DT40. , 2004, DNA repair.

[43]  J. Brugger,et al.  An Oligomerized 53BP1 Tudor Domain Suffices for Recognition of DNA Double-Strand Breaks , 2008, Molecular and Cellular Biology.

[44]  Jiri Bartek,et al.  Human CtIP promotes DNA end resection , 2007, Nature.

[45]  Junjie Chen,et al.  p53 Binding Protein 53BP1 Is Required for DNA Damage Responses and Tumor Suppression in Mice , 2003, Molecular and Cellular Biology.

[46]  T. Ludwig,et al.  BRCA1 functions independently of homologous recombination in DNA interstrand crosslink repair. , 2012, Molecular cell.

[47]  J. Bartek,et al.  The DNA-damage response in human biology and disease , 2009, Nature.

[48]  M. Lieber,et al.  The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway. , 2010, Annual review of biochemistry.

[49]  Vishnu Dileep,et al.  Mouse Rif1 is a key regulator of the replication‐timing programme in mammalian cells , 2012, The EMBO journal.

[50]  L. Symington,et al.  Double-strand break end resection and repair pathway choice. , 2011, Annual review of genetics.

[51]  M. Nussenzweig,et al.  AID targeting in antibody diversity. , 2011, Advances in immunology.

[52]  M. Nussenzweig,et al.  53BP1 facilitates long-range DNA end-joining during V(D)J recombination , 2008, Nature.

[53]  A. Mclaren,et al.  Identification and characterisation of mRif1: A mouse telomere‐associated protein highly expressed in germ cells and embryo‐derived pluripotent stem cells , 2004, Developmental dynamics : an official publication of the American Association of Anatomists.

[54]  Stephen C. West,et al.  Molecular views of recombination proteins and their control , 2003, Nature Reviews Molecular Cell Biology.

[55]  Junjie Chen,et al.  The Tandem BRCT Domain of 53BP1 Is Not Required for Its Repair Function* , 2006, Journal of Biological Chemistry.

[56]  T. Lange,et al.  Shelterin: the protein complex that shapes and safeguards human telomeres , 2005 .

[57]  D. Shore,et al.  Rap1p and telomere length regulation in yeast. , 1997, Ciba Foundation symposium.

[58]  A. Jauch,et al.  DNA Ligase IV-Dependent NHEJ of Deprotected Mammalian Telomeres in G1 and G2 , 2002, Current Biology.

[59]  Alan Ashworth,et al.  Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy , 2005, Nature.

[60]  S. Holland,et al.  Spontaneous Staphylococcus xylosus infection in mice deficient in NADPH oxidase and comparison with other laboratory mouse strains. , 2010, Journal of the American Association for Laboratory Animal Science : JAALAS.

[61]  M. Jasin,et al.  Double-strand breaks and translocations in cancer. , 2002, Cellular and molecular life sciences : CMLS.

[62]  F. Alt,et al.  53BP1 links DNA damage-response pathways to immunoglobulin heavy chain class-switch recombination , 2004, Nature Immunology.

[63]  Anne E Carpenter,et al.  CellProfiler: image analysis software for identifying and quantifying cell phenotypes , 2006, Genome Biology.