CtIP: A DNA damage response protein at the intersection of DNA metabolism.

The mammalian CtIP protein and its orthologs in other eukaryotes promote the resection of DNA double-strand breaks and are essential for meiotic recombination. Here we review the current literature supporting the role of CtIP in DNA end processing and the importance of CtIP endonuclease activity in DNA repair. We also examine the regulation of CtIP function by post-translational modifications, and its involvement in transcription- and replication-dependent functions through association with other protein complexes. The tumor suppressor function of CtIP likely is dependent on a combination of these roles in many aspects of DNA metabolism.

[1]  Stephen P. Jackson,et al.  Human CtIP Mediates Cell Cycle Control of DNA End Resection and Double Strand Break Repair*S⃞ , 2009, Journal of Biological Chemistry.

[2]  Xiaohua Wu,et al.  Cell Cycle-dependent Complex Formation of BRCA1·CtIP·MRN Is Important for DNA Double-strand Break Repair* , 2008, Journal of Biological Chemistry.

[3]  K. Savage,et al.  BRCA1, a ‘complex’ protein involved in the maintenance of genomic stability , 2015, The FEBS journal.

[4]  Gerald R. Smith,et al.  Meiotic DNA Double-Strand Break Repair Requires Two Nucleases, MRN and Ctp1, To Produce a Single Size Class of Rec12 (Spo11)-Oligonucleotide Complexes , 2009, Molecular and Cellular Biology.

[5]  T. Paull,et al.  The 3' to 5' exonuclease activity of Mre 11 facilitates repair of DNA double-strand breaks. , 1998, Molecular cell.

[6]  Y. Pommier,et al.  Tyrosyl-DNA Phosphodiesterase 1 (TDP1) Repairs DNA Damage Induced by Topoisomerases I and II and Base Alkylation in Vertebrate Cells* , 2012, The Journal of Biological Chemistry.

[7]  Y. Shiloh,et al.  Functional link of BRCA1 and ataxia telangiectasia gene product in DNA damage response , 2000, Nature.

[8]  Rohit Prakash,et al.  Mechanism of the ATP-dependent DNA end-resection machinery from Saccharomyces cerevisiae , 2010, Nature.

[9]  P. Huertas,et al.  BRCA1 accelerates CtIP-mediated DNA-end resection. , 2014, Cell reports.

[10]  A. Varma,et al.  Structural basis for cell cycle checkpoint control by the BRCA1-CtIP complex. , 2005, Biochemistry.

[11]  A. Shevchenko,et al.  The Mre11-Rad50-Nbs1 complex mediates activation of TopBP1 by ATM. , 2009, Molecular biology of the cell.

[12]  N. de Leeuw,et al.  A complex microcephaly syndrome in a Pakistani family associated with a novel missense mutation in RBBP8 and a heterozygous deletion in NRXN1. , 2014, Gene.

[13]  S. Jackson,et al.  CtIP tetramer assembly is required for DNA-end resection and repair , 2014, Nature Structural &Molecular Biology.

[14]  O. Murina,et al.  FANCD2 and CtIP cooperate to repair DNA interstrand crosslinks. , 2014, Cell reports.

[15]  R. Schnabel,et al.  A conserved function for a Caenorhabditis elegans Com1/Sae2/CtIP protein homolog in meiotic recombination , 2007, The EMBO journal.

[16]  B. Shafer,et al.  A mechanism of palindromic gene amplification in Saccharomyces cerevisiae. , 2005, Genes & development.

[17]  J. Yeo,et al.  CtIP mediates replication fork recovery in a FANCD2-regulated manner. , 2014, Human molecular genetics.

[18]  R. Ghirlando,et al.  Sae2 is an endonuclease that processes hairpin DNA cooperatively with the Mre11/Rad50/Xrs2 complex. , 2007, Molecular cell.

[19]  Wen-Hwa Lee,et al.  Removal of BRCA1/CtIP/ZBRK1 repressor complex on ANG1 promoter leads to accelerated mammary tumor growth contributed by prominent vasculature. , 2006, Cancer cell.

[20]  S. Prinz,et al.  Isolation of COM1, a new gene required to complete meiotic double-strand break-induced recombination in Saccharomyces cerevisiae. , 1997, Genetics.

[21]  M. Kupiec,et al.  The CDK regulates repair of double‐strand breaks by homologous recombination during the cell cycle , 2004, The EMBO journal.

[22]  Hailong Wang,et al.  Catalytic and noncatalytic roles of the CtIP endonuclease in double-strand break end resection. , 2014, Molecular cell.

[23]  B. Helmink,et al.  H2AX Prevents CtIP-Mediated DNA End Resection and Aberrant Repair in G1-Phase Lymphocytes , 2010, Nature.

[24]  Ralph Scully,et al.  BRCA1 controls homologous recombination at Tus/Ter-stalled mammalian replication forks , 2014, Nature.

[25]  T. Ludwig,et al.  CtIP-mediated resection is essential for viability and can operate independently of BRCA1 , 2014, The Journal of experimental medicine.

[26]  A. Bowcock,et al.  The C-terminal (BRCT) Domains of BRCA1 Interact in Vivo with CtIP, a Protein Implicated in the CtBP Pathway of Transcriptional Repression* , 1998, The Journal of Biological Chemistry.

[27]  María Jesús Fernández-Ávila,et al.  Neddylation inhibits CtIP-mediated resection and regulates DNA double strand break repair pathway choice , 2015, Nucleic acids research.

[28]  F. Liu,et al.  Inactivation of CtIP Leads to Early Embryonic Lethality Mediated by G1 Restraint and to Tumorigenesis by Haploid Insufficiency , 2005, Molecular and Cellular Biology.

[29]  Sang Eun Lee,et al.  Sgs1 Helicase and Two Nucleases Dna2 and Exo1 Resect DNA Double-Strand Break Ends , 2008, Cell.

[30]  J. M. Boyd,et al.  Molecular cloning and characterization of a cellular phosphoprotein that interacts with a conserved C-terminal domain of adenovirus E1A involved in negative modulation of oncogenic transformation. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[31]  Jing He,et al.  CtIP maintains stability at common fragile sites and inverted repeats by end resection-independent endonuclease activity. , 2014, Molecular cell.

[32]  Adam P. Rosebrock,et al.  A cell cycle-dependent regulatory circuit composed of 53BP1-RIF1 and BRCA1-CtIP controls DNA repair pathway choice. , 2013, Molecular cell.

[33]  Miss A.O. Penney.  (b) , 1974, The New Yale Book of Quotations.

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

[35]  William C Earnshaw,et al.  Mutations in pericentrin cause Seckel syndrome with defective ATR-dependent DNA damage signaling , 2008, Nature Genetics.

[36]  Junjie Chen,et al.  BRCA1 ubiquitinates its phosphorylation-dependent binding partner CtIP. , 2006, Genes & development.

[37]  W. Dunphy,et al.  CtIP interacts with TopBP1 and Nbs1 in the response to double-stranded DNA breaks (DSBs) in Xenopus egg extracts , 2011, Cell cycle.

[38]  D. Gordenin,et al.  The Mre11 Complex Is Required for Repair of Hairpin-Capped Double-Strand Breaks and Prevention of Chromosome Rearrangements , 2002, Cell.

[39]  Junjie Chen,et al.  Phosphopeptide Binding Specificities of BRCA1 COOH-terminal (BRCT) Domains* , 2003, Journal of Biological Chemistry.

[40]  Linda Z. Shi,et al.  The Interaction of CtIP and Nbs1 Connects CDK and ATM to Regulate HR–Mediated Double-Strand Break Repair , 2013, PLoS genetics.

[41]  M. Nyegaard,et al.  CtIP Mutations Cause Seckel and Jawad Syndromes , 2011, PLoS genetics.

[42]  Linda Z. Shi,et al.  CtIP Protein Dimerization Is Critical for Its Recruitment to Chromosomal DNA Double-stranded Breaks* , 2012, The Journal of Biological Chemistry.

[43]  Sean V Tavtigian,et al.  Characterization of a carboxy-terminal BRCA1 interacting protein , 1998, Oncogene.

[44]  T. Paull,et al.  Mre11–Rad50–Xrs2 and Sae2 promote 5’ strand resection of DNA double-strand breaks , 2010, Nature Structural &Molecular Biology.

[45]  D. D. Bailey,et al.  Yeast Screens Identify the RNA Polymerase II CTD and SPT5 as Relevant Targets of BRCA1 Interaction , 2008, PloS one.

[46]  K. Georgopoulos,et al.  Ikaros-CtIP Interactions Do Not Require C-terminal Binding Protein and Participate in a Deacetylase-independent Mode of Repression* , 2002, The Journal of Biological Chemistry.

[47]  E. Rosen,et al.  BRCA1 regulation of transcription. , 2006, Cancer letters.

[48]  J. Haber,et al.  Functional Interactions Between Sae2 and the Mre11 Complex , 2008, Genetics.

[49]  Olivia Barton,et al.  CtIP and MRN promote non-homologous end-joining of etoposide-induced DNA double-strand breaks in G1 , 2010, Nucleic acids research.

[50]  Paul Modrich,et al.  BLM-DNA2-RPA-MRN and EXO1-BLM-RPA-MRN constitute two DNA end resection machineries for human DNA break repair. , 2011, Genes & development.

[51]  Wen-Hwa Lee,et al.  CtIP Activates Its Own and Cyclin D1 Promoters via the E2F/RB Pathway during G1/S Progression , 2006, Molecular and Cellular Biology.

[52]  Y. Pommier,et al.  Interfacial inhibitors: targeting macromolecular complexes , 2011, Nature Reviews Drug Discovery.

[53]  Y. Pommier.  DNA Topoisomerase I Inhibitors: Chemistry, Biology, and Interfacial Inhibition , 2009 .

[54]  K. Bremner,et al.  Structural determinants outside the PXDLS sequence affect the interaction of adenovirus E1A, C-terminal interacting protein and Drosophila repressors with C-terminal binding protein. , 2001, Biochimica et biophysica acta.

[55]  J. Petrini,et al.  The MRE11 complex: starting from the ends , 2011, Nature Reviews Molecular Cell Biology.

[56]  Xin Yu,et al.  The LIM Domain Protein LMO4 Interacts with the Cofactor CtIP and the Tumor Suppressor BRCA1 and Inhibits BRCA1 Activity* , 2002, The Journal of Biological Chemistry.

[57]  M. Perucho,et al.  Double strand break repair components are frequent targets of microsatellite instability in endometrial cancer. , 2010, European journal of cancer.

[58]  P. Mullan,et al.  The role of BRCA1 in transcriptional regulation and cell cycle control , 2006, Oncogene.

[59]  A. Llombart‐Bosch,et al.  CtIP Silencing as a Novel Mechanism of Tamoxifen Resistance in Breast Cancer , 2007, Molecular Cancer Research.

[60]  F. Couch,et al.  Modification of BRCA 1-Associated Breast and Ovarian Cancer Risk by BRCA 1-Interacting Genes , 2011 .

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

[62]  Y. Pommier,et al.  Tyrosyl-DNA-phosphodiesterases (TDP1 and TDP2). , 2014, DNA repair.

[63]  B. Gerrits,et al.  Prolyl isomerase PIN1 regulates DNA double-strand break repair by counteracting DNA end resection. , 2013, Molecular cell.

[64]  P. Russell,et al.  Ctp1 is a cell-cycle-regulated protein that functions with Mre11 complex to control double-strand break repair by homologous recombination. , 2007, Molecular cell.

[65]  Yi Zhou,et al.  Quantitation of DNA double-strand break resection intermediates in human cells , 2013, Nucleic acids research.

[66]  B. Chait,et al.  Activation of DSB processing requires phosphorylation of CtIP by ATR. , 2013, Molecular cell.

[67]  Wen-Hwa Lee,et al.  Derepression of HMGA2 via Removal of ZBRK1/BRCA1/CtIP Complex Enhances Mammary Tumorigenesis* , 2009, The Journal of Biological Chemistry.

[68]  Marco Foiani,et al.  DNA end resection, homologous recombination and DNA damage checkpoint activation require CDK1 , 2004, Nature.

[69]  G. Chinnadurai,et al.  CtIP, a candidate tumor susceptibility gene is a team player with luminaries. , 2006, Biochimica et biophysica acta.

[70]  A. Sartori,et al.  APC/CCdh1 controls CtIP stability during the cell cycle and in response to DNA damage , 2014, The EMBO journal.

[71]  Georges Mer,et al.  The BRCT Domain Is a Phospho-Protein Binding Domain , 2003, Science.

[72]  K. Cimprich,et al.  Causes and consequences of replication stress , 2013, Nature Cell Biology.

[73]  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.

[74]  Maximina H. Yun,et al.  CtIP-BRCA1 modulates the choice of DNA double-strand break repair pathway throughout the cell cycle , 2009, Nature.

[75]  Yang Li,et al.  Aberrant Topoisomerase-1-DNA Lesions are Pathogenic in Neurodegenerative Genome Instability Syndromes , 2014, Nature Neuroscience.

[76]  Christian Bailly,et al.  Contemporary challenges in the design of topoisomerase II inhibitors for cancer chemotherapy. , 2012, Chemical reviews.

[77]  Lucy H. Jones,et al.  E. coli SbcCD and RecA Control Chromosomal Rearrangement Induced by an Interrupted Palindrome , 2010, Molecular cell.

[78]  Y. Pommier,et al.  Collaborative Action of Brca1 and CtIP in Elimination of Covalent Modifications from Double-Strand Breaks to Facilitate Subsequent Break Repair , 2010, PLoS genetics.

[79]  M. Resnick,et al.  Tetrameric Ctp1 coordinates DNA binding and bridging in DNA double strand break repair , 2014, Nature Structural &Molecular Biology.

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

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

[82]  F. Couch,et al.  Modification of BRCA1-Associated Breast and Ovarian Cancer Risk by BRCA1-Interacting Genes. , 2011, Cancer research.

[83]  J. Blackwood,et al.  SbcCD causes a double-strand break at a DNA palindrome in the Escherichia coli chromosome. , 2008, Molecular cell.

[84]  J. Nevins,et al.  A mechanism for Rb/p130-mediated transcription repression involving recruitment of the CtBP corepressor. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[85]  R. Rosell,et al.  BRCA1, LMO4, and CtIP mRNA Expression in Erlotinib-Treated Non–Small-Cell Lung Cancer Patients with EGFR Mutations , 2013, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[86]  F. Klein,et al.  A novel plant gene essential for meiosis is related to the human CtIP and the yeast COM1/SAE2 gene , 2007, The EMBO journal.

[87]  J. Champoux.  DNA topoisomerases: structure, function, and mechanism. , 2001, Annual review of biochemistry.

[88]  J. M. Boyd,et al.  Interaction between a Cellular Protein That Binds to the C-terminal Region of Adenovirus E1A (CtBP) and a Novel Cellular Protein Is Disrupted by E1A through a Conserved PLDLS Motif* , 1998, The Journal of Biological Chemistry.

[89]  J. Walter,et al.  BRCA1 promotes unloading of the CMG helicase from a stalled DNA replication fork. , 2014, Molecular cell.

[90]  J. Visvader,et al.  Dimerization of CtIP, a BRCA1- and CtBP-interacting Protein, Is Mediated by an N-terminal Coiled-coil Motif* , 2004, Journal of Biological Chemistry.

[91]  Y. Pommier,et al.  Interfacial inhibitors of protein-nucleic acid interactions. , 2005, Current medicinal chemistry. Anti-cancer agents.

[92]  P. Cejka,et al.  Sae2 promotes dsDNA endonuclease activity within Mre11–Rad50–Xrs2 to resect DNA breaks , 2014, Nature.

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

[94]  M. J. Neale,et al.  Distinct requirements for the Rad32(Mre11) nuclease and Ctp1(CtIP) in the removal of covalently bound topoisomerase I and II from DNA. , 2009, Molecular cell.

[95]  R. Baer,et al.  Nuclear Localization and Cell Cycle-specific Expression of CtIP, a Protein That Associates with the BRCA1 Tumor Suppressor* , 2000, The Journal of Biological Chemistry.

[96]  Eleni P. Mimitou,et al.  Sae2, Exo1 and Sgs1 collaborate in DNA double-strand break processing , 2008, Nature.

[97]  Y. Pommier,et al.  Interfacial inhibition of macromolecular interactions: nature's paradigm for drug discovery. , 2005, Trends in pharmacological sciences.

[98]  J. Wang,et al.  Supercoiling of the DNA template during transcription. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[99]  Junjie Chen,et al.  DNA Damage-Induced Cell Cycle Checkpoint Control Requires CtIP, a Phosphorylation-Dependent Binding Partner of BRCA1 C-Terminal Domains , 2004, Molecular and Cellular Biology.

[100]  Andrew H. Z. McKee,et al.  A general method for identifying recessive diploid-specific mutations in Saccharomyces cerevisiae, its application to the isolation of mutants blocked at intermediate stages of meiotic prophase and characterization of a new gene SAE2. , 1997, Genetics.

[101]  L. Aaltonen,et al.  Screening for microsatellite instability target genes in colorectal cancers , 2002, Journal of medical genetics.

[102]  T. Ha,et al.  The SOSS1 single‐stranded DNA binding complex promotes DNA end resection in concert with Exo1 , 2012, The EMBO journal.

[103]  M. J. Neale,et al.  Endonucleolytic processing of covalent protein-linked DNA double-strand breaks , 2005, Nature.

[104]  H. Kurumizaka,et al.  FANCD2 binds CtIP and regulates DNA-end resection during DNA interstrand crosslink repair. , 2014, Cell reports.

[105]  Xingzhi Xu,et al.  CtIP is required for DNA damage-dependent induction of P21 , 2013, Cell cycle.

[106]  K. Cimprich,et al.  A role for the MRN complex in ATR activation via TOPBP1 recruitment. , 2013, Molecular cell.

[107]  R. Ganapathi,et al.  DNA topoisomerase II enzymes as molecular targets for cancer chemotherapy. , 2010, Current cancer drug targets.

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

[109]  Junjie Chen,et al.  N Terminus of CtIP Is Critical for Homologous Recombination-mediated Double-strand Break Repair* , 2009, The Journal of Biological Chemistry.

[110]  M. Ruíz-Borrego,et al.  Prognostic value of CtIP/RBBP8 expression in breast cancer , 2013, Cancer medicine.

[111]  N. Curtin,et al.  Microsatellite instability induced mutations in DNA repair genes CtIP and MRE11 confer hypersensitivity to poly (ADP-ribose) polymerase inhibitors in myeloid malignancies , 2013, Haematologica.

[112]  R. Rothstein,et al.  Phosphorylation-Regulated Transitions in an Oligomeric State Control the Activity of the Sae2 DNA Repair Enzyme , 2013, Molecular and Cellular Biology.

[113]  S. Jackson,et al.  Human SIRT6 Promotes DNA End Resection Through CtIP Deacetylation , 2010, Science.

[114]  M. Steinlage,et al.  Polo-like kinase 3 regulates CtIP during DNA double-strand break repair in G1 , 2014, The Journal of cell biology.

[115]  Linda Z. Shi,et al.  CtIP links DNA double-strand break sensing to resection. , 2009, Molecular cell.

[116]  A. Reymond,et al.  Molecular cloning and characterization of a novel retinoblastoma-binding protein. , 1998, Genomics.

[117]  John A. Tainer,et al.  Nbs1 Flexibly Tethers Ctp1 and Mre11-Rad50 to Coordinate DNA Double-Strand Break Processing and Repair , 2009, Cell.

[118]  Jung S. Byun,et al.  C-Terminal Binding Protein: A Molecular Link between Metabolic Imbalance and Epigenetic Regulation in Breast Cancer , 2013, International journal of cell biology.

[119]  Jiri Bartek,et al.  ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks , 2006, Nature Cell Biology.