Nonhomologous end joining: a good solution for bad ends.

Double strand breaks pose unique problems for DNA repair, especially when broken ends possess complex structures that interfere with standard DNA transactions. Nonhomologous end joining can use multiple strategies to solve these problems. It further uses sophisticated means to ensure the strategy chosen provides the ideal balance of flexibility and accuracy.

[1]  Katheryn Meek,et al.  Chapter 2 DNA-PK , 2008 .

[2]  S. Jackson,et al.  The DNA-dependent protein kinase: Requirement for DNA ends and association with Ku antigen , 1993, Cell.

[3]  D. Ramsden,et al.  Specificity of the dRP/AP Lyase of Ku Promotes Nonhomologous End Joining (NHEJ) Fidelity at Damaged Ends* , 2012, The Journal of Biological Chemistry.

[4]  J. Krahn,et al.  Structure of an Aprataxin–DNA complex with insights into AOA1 Neurodegenerative Disease , 2011, Nature Structural &Molecular Biology.

[5]  T. E. Wilson,et al.  Mutations of the Yku80 C Terminus and Xrs2 FHA Domain Specifically Block Yeast Nonhomologous End Joining , 2005, Molecular and Cellular Biology.

[6]  C. Berek,et al.  Immunoglobulin kappa light chain gene rearrangement is impaired in mice deficient for DNA polymerase mu. , 2003, Immunity.

[7]  G. M. Wilson,et al.  Distinct kinetics of human DNA ligases I, IIIalpha, IIIbeta, and IV reveal direct DNA sensing ability and differential physiological functions in DNA repair. , 2009, DNA repair.

[8]  T. Paull,et al.  A mechanistic basis for Mre11-directed DNA joining at microhomologies. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[9]  Chun-Yuan Ting,et al.  26 S Proteasome-mediated Degradation of Topoisomerase II Cleavable Complexes* , 2001, The Journal of Biological Chemistry.

[10]  A. Burgin,et al.  A eukaryotic enzyme that can disjoin dead-end covalent complexes between DNA and type I topoisomerases. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[11]  Yunmei Ma,et al.  The Artemis:DNA-PKcs endonuclease cleaves DNA loops, flaps, and gaps. , 2005, DNA repair.

[12]  K. Caldecott,et al.  APLF (C2orf13) Is a Novel Human Protein Involved in the Cellular Response to Chromosomal DNA Strand Breaks , 2007, Molecular and Cellular Biology.

[13]  Chen Wang,et al.  Phosphorylation of polynucleotide kinase/ phosphatase by DNA-dependent protein kinase and ataxia-telangiectasia mutated regulates its association with sites of DNA damage , 2011, Nucleic acids research.

[14]  J. Nitiss.  Targeting DNA topoisomerase II in cancer chemotherapy , 2009, Nature Reviews Cancer.

[15]  M. Lieber,et al.  A noncatalytic function of the ligation complex during nonhomologous end joining , 2013, The Journal of cell biology.

[16]  F. Strauss,et al.  Analysis of the mechanism of interaction of simian Ku protein with DNA. , 1991, Nucleic acids research.

[17]  D. Durocher,et al.  The molecular architecture of the mammalian DNA repair enzyme, polynucleotide kinase. , 2005, Molecular cell.

[18]  C. Anderson,et al.  Human cells contain a DNA-activated protein kinase that phosphorylates simian virus 40 T antigen, mouse p53, and the human Ku autoantigen , 1990, Molecular and cellular biology.

[19]  J. Menetski,et al.  V(D)J recombination: Broken DNA molecules with covalently sealed (hairpin) coding ends in scid mouse thymocytes , 1992, Cell.

[20]  D. Ramsden,et al.  Ku Recruits the XRCC4-Ligase IV Complex to DNA Ends , 2000, Molecular and Cellular Biology.

[21]  K. Datta,et al.  Base Damage Immediately Upstream from Double-Strand Break Ends is a More Severe Impediment to Nonhomologous End Joining than Blocked 3′-Termini , 2011, Radiation research.

[22]  K. Caldecott,et al.  A human 5′-tyrosyl DNA phosphodiesterase that repairs topoisomerase-mediated DNA damage , 2009, Nature.

[23]  B. Reina-San-Martin,et al.  PARP-3 and APLF function together to accelerate nonhomologous end-joining. , 2011, Molecular cell.

[24]  A. Tomkinson,et al.  Human Mre11/Human Rad50/Nbs1 and DNA Ligase IIIα/XRCC1 Protein Complexes Act Together in an Alternative Nonhomologous End Joining Pathway* , 2011, The Journal of Biological Chemistry.

[25]  Z. Zeng,et al.  APLF promotes the assembly and activity of non‐homologous end joining protein complexes , 2012, The EMBO journal.

[26]  Martin Kühne,et al.  A pathway of double-strand break rejoining dependent upon ATM, Artemis, and proteins locating to gamma-H2AX foci. , 2004, Molecular cell.

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

[28]  J. Steitz,et al.  Characterization of the DNA-binding protein antigen Ku recognized by autoantibodies from patients with rheumatic disorders. , 1986, The Journal of biological chemistry.

[29]  J. Champoux,et al.  Human Tdp1 Cleaves a Broad Spectrum of Substrates, Including Phosphoamide Linkages* , 2005, Journal of Biological Chemistry.

[30]  D. Ramsden,et al.  Association of DNA Polymerase μ (pol μ) with Ku and Ligase IV: Role for pol μ in End-Joining Double-Strand Break Repair , 2002, Molecular and Cellular Biology.

[31]  D. Ramsden,et al.  End-bridging is required for pol μ to efficiently promote repair of noncomplementary ends by nonhomologous end joining , 2008, Nucleic acids research.

[32]  P. Jeggo,et al.  The C Terminus of Ku80 Activates the DNA-Dependent Protein Kinase Catalytic Subunit , 1999, Molecular and Cellular Biology.

[33]  Qi Ding,et al.  Non-homologous End Joining Requires That the DNA-PK Complex Undergo an Autophosphorylation-dependent Rearrangement at DNA Ends* , 2004, Journal of Biological Chemistry.

[34]  W. Dynan,et al.  Interaction of Ku protein and DNA-dependent protein kinase catalytic subunit with nucleic acids. , 1998, Nucleic acids research.

[35]  Yunmei Ma,et al.  Functional and biochemical dissection of the structure‐specific nuclease ARTEMIS , 2004, The EMBO journal.

[36]  S. Soubeyrand,et al.  Artemis phosphorylated by DNA-dependent protein kinase associates preferentially with discrete regions of chromatin. , 2006, Journal of molecular biology.

[37]  P. Wu,et al.  Structural and Functional Interaction between the Human DNA Repair Proteins DNA Ligase IV and XRCC4 , 2009, Molecular and Cellular Biology.

[38]  A. Fischer,et al.  Artemis, a Novel DNA Double-Strand Break Repair/V(D)J Recombination Protein, Is Mutated in Human Severe Combined Immune Deficiency , 2001, Cell.

[39]  S. Lees-Miller,et al.  XRCC4's interaction with XLF is required for coding (but not signal) end joining , 2012, Nucleic acids research.

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

[41]  C. Wyman,et al.  A human XRCC4–XLF complex bridges DNA , 2012, Nucleic acids research.

[42]  David J. Chen,et al.  Functional significance of the interaction with Ku in DNA double‐strand break recognition of XLF , 2011, FEBS letters.

[43]  S. Nakajima,et al.  A novel human AP endonuclease with conserved zinc‐finger‐like motifs involved in DNA strand break responses , 2007, The EMBO journal.

[44]  J. Lupski,et al.  Deficiency in 3′-phosphoglycolate processing in human cells with a hereditary mutation in tyrosyl-DNA phosphodiesterase (TDP1) , 2005, Nucleic acids research.

[45]  D. Ramsden,et al.  Trimming of damaged 3' overhangs of DNA double-strand breaks by the Metnase and Artemis endonucleases. , 2013, DNA repair.

[46]  D. Ramsden,et al.  Dual Modes of Interaction between XRCC4 and Polynucleotide Kinase/Phosphatase , 2010, The Journal of Biological Chemistry.

[47]  David J. Chen,et al.  DNA-PK and ATM phosphorylation sites in XLF/Cernunnos are not required for repair of DNA double strand breaks. , 2008, DNA repair.

[48]  Stephen P. Jackson,et al.  Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage , 2005, Nature.

[49]  Yunmei Ma,et al.  A biochemically defined system for mammalian nonhomologous DNA end joining. , 2004, Molecular cell.

[50]  Yunmei Ma,et al.  Repair of Double-Strand DNA Breaks by the Human Nonhomologous DNA End Joining Pathway: The Iterative Processing Model , 2005, Cell cycle.

[51]  L. Harrison,et al.  Apex1 can cleave complex clustered DNA lesions in cells. , 2009, DNA repair.

[52]  David J. Chen,et al.  Ataxia Telangiectasia Mutated (ATM) Is Essential for DNA-PKcs Phosphorylations at the Thr-2609 Cluster upon DNA Double Strand Break* , 2007, Journal of Biological Chemistry.

[53]  B. L. Sibanda,et al.  Crystal Structure of DNA-PKcs Reveals a Large Open-Ring Cradle Comprised of HEAT Repeats , 2009, Nature.

[54]  T. E. Wilson,et al.  DNA Joint Dependence of Pol X Family Polymerase Action in Nonhomologous End Joining* , 2005, Journal of Biological Chemistry.

[55]  T. Kunkel,et al.  A closed conformation for the Pol λ catalytic cycle , 2005, Nature Structural &Molecular Biology.

[56]  Qi Ding,et al.  trans Autophosphorylation at DNA-Dependent Protein Kinase's Two Major Autophosphorylation Site Clusters Facilitates End Processing but Not End Joining , 2007, Molecular and Cellular Biology.

[57]  Lucio Comai,et al.  Functional Interaction between Ku and the Werner Syndrome Protein in DNA End Processing* , 2000, The Journal of Biological Chemistry.

[58]  Kefei Yu,et al.  Apurinic/Apyrimidinic Endonuclease 1 Is the Essential Nuclease during Immunoglobulin Class Switch Recombination , 2013, Molecular and Cellular Biology.

[59]  G. Chu,et al.  Cernunnos/XLF promotes the ligation of mismatched and noncohesive DNA ends , 2007, Proceedings of the National Academy of Sciences.

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

[61]  G. Chu,et al.  Cooperative Assembly of a Protein-DNA Filament for Nonhomologous End Joining* , 2013, The Journal of Biological Chemistry.

[62]  M. Lieber,et al.  Activity of DNA ligase IV stimulated by complex formation with XRCC4 protein in mammalian cells , 1997, Nature.

[63]  B. Schmidt,et al.  All tangled up: how cells direct, manage and exploit topoisomerase function , 2011, Nature Reviews Molecular Cell Biology.

[64]  R. Guérois,et al.  Delineation of the Xrcc4-interacting Region in the Globular Head Domain of Cernunnos/XLF* , 2010, The Journal of Biological Chemistry.

[65]  E. Koonin,et al.  SAP - a putative DNA-binding motif involved in chromosomal organization. , 2000, Trends in biochemical sciences.

[66]  J. Tainer,et al.  XLF regulates filament architecture of the XRCC4·ligase IV complex. , 2010, Structure.

[67]  R. Leber,et al.  The XRCC4 Gene Product Is a Target for and Interacts with the DNA-dependent Protein Kinase* , 1998, The Journal of Biological Chemistry.

[68]  Yunmei Ma,et al.  DNA-PKcs Dependence of Artemis Endonucleolytic Activity, Differences between Hairpins and 5′ or 3′ Overhangs* , 2006, Journal of Biological Chemistry.

[69]  David J. Chen,et al.  Requirement for XLF/Cernunnos in alignment-based gap filling by DNA polymerases λ and μ for nonhomologous end joining in human whole-cell extracts , 2009, Nucleic acids research.

[70]  J. Mornon,et al.  Metallo-β-lactamase fold within nucleic acids processing enzymes: the β-CASP family , 2002 .

[71]  Romain Chayot,et al.  DNA polymerase μ is a global player in the repair of non-homologous end-joining substrates. , 2012, DNA repair.

[72]  S. Jackson,et al.  Mapping of protein-protein interactions within the DNA-dependent protein kinase complex. , 1999, Nucleic acids research.

[73]  T. Kirchhoff,et al.  DNA polymerase mu (Pol mu), homologous to TdT, could act as a DNA mutator in eukaryotic cells. , 2000, The EMBO journal.

[74]  H. Erdjument-Bromage,et al.  Artemis C-terminal region facilitates V(D)J recombination through its interactions with DNA Ligase IV and DNA-PKcs , 2012, The Journal of experimental medicine.

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

[76]  K. Valerie,et al.  Tyrosyl-DNA phosphodiesterase and the repair of 3'-phosphoglycolate-terminated DNA double-strand breaks. , 2009, DNA repair.

[77]  S. Scherer,et al.  Molecular Cloning of the Human Gene, PNKP, Encoding a Polynucleotide Kinase 3′-Phosphatase and Evidence for Its Role in Repair of DNA Strand Breaks Caused by Oxidative Damage* , 1999, The Journal of Biological Chemistry.

[78]  T. Blundell,et al.  Structure of the Catalytic Region of DNA Ligase IV in Complex with an Artemis Fragment Sheds Light on Double-Strand Break Repair , 2013, Structure.

[79]  L. Loeb,et al.  Werner Syndrome Protein , 1998, The Journal of Biological Chemistry.

[80]  D. Ramsden,et al.  Ku heterodimer binds to both ends of the Werner protein and functional interaction occurs at the Werner N-terminus. , 2002, Nucleic acids research.

[81]  F. Delbos,et al.  Two novel human and mouse DNA polymerases of the polX family. , 2000, Nucleic acids research.

[82]  K. Caldecott.  Tyrosyl DNA phosphodiesterase 2, an enzyme fit for purpose , 2012, Nature Structural &Molecular Biology.

[83]  I. Villey,et al.  The Metallo-β-Lactamase/β-CASP Domain of Artemis Constitutes the Catalytic Core for V(D)J Recombination , 2004, The Journal of experimental medicine.

[84]  John A Tainer,et al.  A structural model for regulation of NHEJ by DNA-PKcs autophosphorylation. , 2010, DNA repair.

[85]  I. Saira Mian,et al.  The premature ageing syndrome protein, WRN, is a 3′→5′ exonuclease , 1998, Nature Genetics.

[86]  Samuel H. Wilson,et al.  DNA Polymerases β and λ Mediate Overlapping and Independent Roles in Base Excision Repair in Mouse Embryonic Fibroblasts , 2010, PloS one.

[87]  J. Hoeijmakers,et al.  The role of DNA dependent protein kinase in synapsis of DNA ends , 2003, Nucleic acids research.

[88]  L. Blanco,et al.  Altered Hematopoiesis in Mice Lacking DNA Polymerase μ Is Due to Inefficient Double-Strand Break Repair , 2009, PLoS genetics.

[89]  A. Fischer,et al.  Phosphorylation of Artemis following irradiation‐induced DNA damage , 2004, European journal of immunology.

[90]  R. Ghirlando,et al.  Crystal structure of the Xrcc4 DNA repair protein and implications for end joining , 2000, The EMBO journal.

[91]  R. Hromas,et al.  Biochemical characterization of metnase's endonuclease activity and its role in NHEJ repair. , 2011, Biochemistry.

[92]  J. Pascal,et al.  PARP-1 mechanism for coupling DNA damage detection to poly(ADP-ribose) synthesis. , 2013, Current opinion in structural biology.

[93]  T. Owen-Hughes,et al.  DNA repair factor APLF is a histone chaperone. , 2011, Molecular cell.

[94]  S. West,et al.  Molecular Mechanism of DNA Deadenylation by the Neurological Disease Protein Aprataxin* , 2008, Journal of Biological Chemistry.

[95]  J. Glover,et al.  Structural basis for the phosphatase activity of polynucleotide kinase/phosphatase on single- and double-stranded DNA substrates , 2011, Proceedings of the National Academy of Sciences.

[96]  P. Russell,et al.  Mre11 Dimers Coordinate DNA End Bridging and Nuclease Processing in Double-Strand-Break Repair , 2008, Cell.

[97]  A. Tomkinson,et al.  Eukaryotic DNA ligases: structural and functional insights. , 2008, Annual review of biochemistry.

[98]  Keith W. Caldecott,et al.  Single-strand break repair and genetic disease , 2008, Nature Reviews Genetics.

[99]  Samuel H. Wilson,et al.  DNA Polymerase λ Mediates a Back-up Base Excision Repair Activity in Extracts of Mouse Embryonic Fibroblasts* , 2005, Journal of Biological Chemistry.

[100]  J. Walker,et al.  Structure of the Ku heterodimer bound to DNA and its implications for double-strand break repair , 2001, Nature.

[101]  G. Chu,et al.  Crystal structure of human XLF: a twist in nonhomologous DNA end-joining. , 2007, Molecular cell.

[102]  P. Jeggo,et al.  DNA‐PK autophosphorylation facilitates Artemis endonuclease activity , 2006, The EMBO journal.

[103]  Y. Shiloh.  ATM and related protein kinases: safeguarding genome integrity , 2003, Nature Reviews Cancer.

[104]  S. West,et al.  The neurodegenerative disease protein aprataxin resolves abortive DNA ligation intermediates , 2006, Nature.

[105]  A. Aggarwal,et al.  Structural basis of DNA ligase IV-Artemis interaction in nonhomologous end-joining. , 2012, Cell reports.

[106]  R. Ghirlando,et al.  Tetramerization and DNA ligase IV interaction of the DNA double-strand break repair protein XRCC4 are mutually exclusive. , 2003, Journal of molecular biology.

[107]  J. Pouliot,et al.  Pathways for repair of topoisomerase I covalent complexes in Saccharomyces cerevisiae , 2001, Genes to cells : devoted to molecular & cellular mechanisms.

[108]  L. Povirk,et al.  Processing of 3′-Phosphoglycolate-terminated DNA Double Strand Breaks by Artemis Nuclease* , 2006, Journal of Biological Chemistry.

[109]  M. Pelikán,et al.  Mechanism of DNA substrate recognition by the mammalian DNA repair enzyme, Polynucleotide Kinase , 2009, Nucleic acids research.

[110]  K. Caldecott,et al.  APLF (C2orf13) Is a Novel Component of Poly(ADP-Ribose) Signaling in Mammalian Cells , 2008, Molecular and Cellular Biology.

[111]  E. Friedberg,et al.  DNA damage and repair , 2003, Nature.

[112]  K. Schwarz,et al.  Single-stranded DNA ligation and XLF-stimulated incompatible DNA end ligation by the XRCC4-DNA ligase IV complex: influence of terminal DNA sequence , 2007, Nucleic acids research.

[113]  L. Povirk,et al.  Accurate in Vitro End Joining of a DNA Double Strand Break with Partially Cohesive 3′-Overhangs and 3′-Phosphoglycolate Termini , 2001, The Journal of Biological Chemistry.

[114]  J. Ward,et al.  The complexity of DNA damage: relevance to biological consequences. , 1994, International journal of radiation biology.

[115]  R. Hromas,et al.  Methylation of histone H3 lysine 36 enhances DNA repair by nonhomologous end-joining , 2010, Proceedings of the National Academy of Sciences.

[116]  R. Hromas,et al.  The human set and transposase domain protein Metnase interacts with DNA Ligase IV and enhances the efficiency and accuracy of non-homologous end-joining. , 2008, DNA repair.

[117]  T. Kunkel,et al.  Implication of DNA Polymerase λ in Alignment-based Gap Filling for Nonhomologous DNA End Joining in Human Nuclear Extracts* , 2004, Journal of Biological Chemistry.

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

[119]  P. Karmakar,et al.  A functional interaction of Ku with Werner exonuclease facilitates digestion of damaged DNA. , 2001, Nucleic acids research.

[120]  D. Ramsden,et al.  Ku is a 5'dRP/AP lyase that excises nucleotide damage near broken ends , 2010, Nature.

[121]  Roger Woodgate,et al.  Y-family DNA polymerases and their role in tolerance of cellular DNA damage , 2012, Nature Reviews Molecular Cell Biology.

[122]  S. Jackson,et al.  XLF Interacts with the XRCC4-DNA Ligase IV Complex to Promote DNA Nonhomologous End-Joining , 2006, Cell.

[123]  W. Haseltine,et al.  gamma Ray induced deoxyribonucleic acid strand breaks. 3' Glycolate termini. , 1983, The Journal of biological chemistry.

[124]  P. Jeggo,et al.  Interaction of the Ku heterodimer with the DNA ligase IV/Xrcc4 complex and its regulation by DNA-PK. , 2007, DNA repair.

[125]  D. Durocher,et al.  Xrcc4 physically links DNA end processing by polynucleotide kinase to DNA ligation by DNA ligase IV , 2004, The EMBO journal.

[126]  J. Griffith,et al.  Synapsis of DNA ends by DNA‐dependent protein kinase , 2002, The EMBO journal.

[127]  L. Povirk,et al.  Conversion of Phosphoglycolate to Phosphate Termini on 3′ Overhangs of DNA Double Strand Breaks by the Human Tyrosyl-DNA Phosphodiesterase hTdp1* , 2002, The Journal of Biological Chemistry.

[128]  B. L. Sibanda,et al.  Crystal structure of an Xrcc4–DNA ligase IV complex , 2001, Nature Structural Biology.

[129]  P. Sung,et al.  Nuclease Activities in a Complex of Human Recombination and DNA Repair Factors Rad50, Mre11, and p95* , 1998, The Journal of Biological Chemistry.

[130]  Takashi Kohno,et al.  Polynucleotide Kinase and Aprataxin-like Forkhead-associated Protein (PALF) Acts as Both a Single-stranded DNA Endonuclease and a Single-Stranded DNA 3′ Exonuclease and Can Participate in DNA End Joining in a Biochemical System* , 2011, The Journal of Biological Chemistry.

[131]  D. Huylebroeck,et al.  TDP2–Dependent Non-Homologous End-Joining Protects against Topoisomerase II–Induced DNA Breaks and Genome Instability in Cells and In Vivo , 2013, PLoS genetics.

[132]  T. Kunkel,et al.  A gradient of template dependence defines distinct biological roles for family X polymerases in nonhomologous end joining. , 2005, Molecular cell.

[133]  C. Delteil,et al.  Coordinated assembly of Ku and p460 subunits of the DNA-dependent protein kinase on DNA ends is necessary for XRCC4-ligase IV recruitment. , 2003, Journal of molecular biology.

[134]  M. Delarue,et al.  Conferring a template-dependent polymerase activity to terminal deoxynucleotidyltransferase by mutations in the Loop1 region , 2009, Nucleic acids research.

[135]  C. Brenner,et al.  The ataxia-oculomotor apraxia 1 gene product has a role distinct from ATM and interacts with the DNA strand break repair proteins XRCC1 and XRCC4. , 2004, DNA repair.

[136]  B. L. Sibanda,et al.  Crystal structure of human XLF/Cernunnos reveals unexpected differences from XRCC4 with implications for NHEJ , 2007, The EMBO journal.

[137]  John A. Murphy,et al.  Reactions of oxyl radicals with DNA. , 1995, Free radical biology & medicine.

[138]  M. Lieber,et al.  DNA ligase IV binds to XRCC4 via a motif located between rather than within its BRCT domains , 1998, Current Biology.

[139]  C. Koch,et al.  Identification and Functional Characterization of a Ku-binding Motif in Aprataxin Polynucleotide Kinase/Phosphatase-like Factor (APLF)* , 2013, The Journal of Biological Chemistry.

[140]  Samuel H. Wilson,et al.  Interplay between DNA polymerases β and λ in repair of oxidation DNA damage in chicken DT40 cells , 2007 .

[141]  D. Ramsden,et al.  Werner Protein Is a Target of DNA-dependent Protein Kinase in Vivo and in Vitro, and Its Catalytic Activities Are Regulated by Phosphorylation* , 2002, The Journal of Biological Chemistry.

[142]  A. Tomkinson,et al.  Structure and function of mammalian DNA ligases. , 1998, Mutation research.

[143]  Yunmei Ma,et al.  Hairpin Opening and Overhang Processing by an Artemis/DNA-Dependent Protein Kinase Complex in Nonhomologous End Joining and V(D)J Recombination , 2002, Cell.

[144]  D. Durocher,et al.  APLF (C2orf13) facilitates nonhomologous end-joining and undergoes ATM-dependent hyperphosphorylation following ionizing radiation. , 2008, DNA repair.

[145]  A. Tomkinson,et al.  Interactions of the DNA Ligase IV-XRCC4 Complex with DNA Ends and the DNA-dependent Protein Kinase* , 2000, The Journal of Biological Chemistry.

[146]  S. Lees-Miller,et al.  DNA-PK: the means to justify the ends? , 2008, Advances in immunology.

[147]  M. Gray,et al.  The Werner syndrome protein is a DNA helicase , 1997, Nature Genetics.

[148]  W. Heyer,et al.  Regulation of homologous recombination in eukaryotes. , 2010, Annual review of genetics.

[149]  D. Chan,et al.  Werner syndrome protein is regulated and phosphorylated by DNA-dependent protein kinase. , 2001, The Journal of biological chemistry.

[150]  Peter O'Neill,et al.  Interplay of two major repair pathways in the processing of complex double-strand DNA breaks. , 2008, DNA repair.

[151]  A. Griffith,et al.  Binding of Ku protein to DNA. Measurement of affinity for ends and demonstration of binding to nicks. , 1993, The Journal of biological chemistry.

[152]  C. Papanicolaou,et al.  Crystal structures of a template‐independent DNA polymerase: murine terminal deoxynucleotidyltransferase , 2002, The EMBO journal.

[153]  Andres A. Larrea,et al.  Template strand scrunching during DNA gap repair synthesis by human polymerase lambda. , 2009, Nature structural & molecular biology.

[154]  D. Ramsden,et al.  Ku complex interacts with and stimulates the Werner protein. , 2000, Genes & development.

[155]  D. Ramsden,et al.  A specific loop in human DNA polymerase mu allows switching between creative and DNA-instructed synthesis , 2006, Nucleic acids research.

[156]  J. Kearney,et al.  Terminal deoxynucleotidyl transferase and repertoire development , 2000, Immunological reviews.

[157]  D T Goodhead,et al.  Initial events in the cellular effects of ionizing radiations: clustered damage in DNA. , 1994, International journal of radiation biology.

[158]  P. Russell,et al.  Release of Ku and MRN from DNA Ends by Mre11 Nuclease Activity and Ctp1 Is Required for Homologous Recombination Repair of Double-Strand Breaks , 2011, PLoS genetics.

[159]  T. Lindahl,et al.  DNA Ligase IV from HeLa Cell Nuclei* , 1996, The Journal of Biological Chemistry.

[160]  B. Bertocci,et al.  Nonoverlapping functions of DNA polymerases mu, lambda, and terminal deoxynucleotidyltransferase during immunoglobulin V(D)J recombination in vivo. , 2006, Immunity.

[161]  R. Guérois,et al.  Structural characterization of filaments formed by human Xrcc4–Cernunnos/XLF complex involved in nonhomologous DNA end-joining , 2011, Proceedings of the National Academy of Sciences.

[162]  A. Tomkinson,et al.  Promotion of Dnl4-catalyzed DNA end-joining by the Rad50/Mre11/Xrs2 and Hdf1/Hdf2 complexes. , 2001, Molecular cell.