Repair of ionizing radiation-induced DNA double-strand breaks by non-homologous end-joining.

DNA DSBs (double-strand breaks) are considered the most cytotoxic type of DNA lesion. They can be introduced by external sources such as IR (ionizing radiation), by chemotherapeutic drugs such as topoisomerase poisons and by normal biological processes such as V(D)J recombination. If left unrepaired, DSBs can cause cell death. If misrepaired, DSBs may lead to chromosomal translocations and genomic instability. One of the major pathways for the repair of IR-induced DSBs in mammalian cells is NHEJ (non-homologous end-joining). The main proteins required for NHEJ in mammalian cells are the Ku heterodimer (Ku70/80 heterodimer), DNA-PKcs [the catalytic subunit of DNA-PK (DNA-dependent protein kinase)], Artemis, XRCC4 (X-ray-complementing Chinese hamster gene 4), DNA ligase IV and XLF (XRCC4-like factor; also called Cernunnos). Additional proteins, including DNA polymerases mu and lambda, PNK (polynucleotide kinase) and WRN (Werner's Syndrome helicase), may also play a role. In the present review, we will discuss our current understanding of the mechanism of NHEJ in mammalian cells and discuss the roles of DNA-PKcs and DNA-PK-mediated phosphorylation in NHEJ.

[1]  P. Jeggo,et al.  Artemis links ATM to Double Strand Break Rejoining , 2005, Cell cycle.

[2]  David J. Chen,et al.  Autophosphorylation of the DNA-dependent protein kinase catalytic subunit is required for rejoining of DNA double-strand breaks. , 2002, Genes & development.

[3]  F. Alt,et al.  Leaky Scid phenotype associated with defective V(D)J coding end processing in Artemis-deficient mice. , 2002, Molecular cell.

[4]  M. Chovanec,et al.  Non-homologous end-joining factors of Saccharomyces cerevisiae. , 2004, FEMS microbiology reviews.

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

[6]  Qi Ding,et al.  DNA-PK phosphorylation sites in XRCC4 are not required for survival after radiation or for V(D)J recombination. , 2003, DNA repair.

[7]  D. Ramsden,et al.  A comparison of BRCT domains involved in nonhomologous end-joining: introducing the solution structure of the BRCT domain of polymerase lambda. , 2008, DNA repair.

[8]  M. Gellert,et al.  DNA binding of Xrcc4 protein is associated with V(D)J recombination but not with stimulation of DNA ligase IV activity , 1999, The EMBO journal.

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

[10]  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.

[11]  Pablo Chacón,et al.  Visualization of DNA‐induced conformational changes in the DNA repair kinase DNA‐PKcs , 2003, The EMBO journal.

[12]  R. Zhao,et al.  TopBP1 activates ATR through ATRIP and a PIKK regulatory domain. , 2008, Genes & development.

[13]  J. Wang,et al.  DNA looping by Ku and the DNA-dependent protein kinase. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[14]  Shunichi Takeda,et al.  Ctp1/CtIP and the MRN complex collaborate in the initial steps of homologous recombination. , 2007, Molecular cell.

[15]  P O'Neill,et al.  Securing genome stability by orchestrating DNA repair: removal of radiation-induced clustered lesions in DNA. , 2001, BioEssays : news and reviews in molecular, cellular and developmental biology.

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

[17]  R. Monnat,et al.  Roles of ATM and NBS1 in chromatin structure modulation and DNA double-strand break repair , 2007, Nature Cell Biology.

[18]  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.

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

[20]  J. Hoeijmakers.  Genome maintenance mechanisms for preventing cancer , 2001, Nature.

[21]  V. Bohr,et al.  Human premature aging, DNA repair and RecQ helicases , 2007, Nucleic acids research.

[22]  Manabu Koike,et al.  Dimerization, translocation and localization of Ku70 and Ku80 proteins. , 2002, Journal of radiation research.

[23]  Y. Hosoi,et al.  Cleavage and phosphorylation of XRCC4 protein induced by X‐irradiation , 2000, FEBS letters.

[24]  J. Turchi,et al.  DNA-dependent conformational changes in the Ku heterodimer. , 2008, Biochemistry.

[25]  D. Chan,et al.  The Protein Kinase CK2 Facilitates Repair of Chromosomal DNA Single-Strand Breaks , 2004, Cell.

[26]  F. Alt,et al.  Mechanism and control of V(D)J recombination versus class switch recombination: similarities and differences. , 2005, Advances in immunology.

[27]  William Arbuthnot Sir Lane,et al.  Phosphorylation and Regulation of DNA Ligase IV Stability by DNA-dependent Protein Kinase* , 2004, Journal of Biological Chemistry.

[28]  David J. Chen,et al.  Defining interactions between DNA-PK and ligase IV/XRCC4. , 2002, DNA repair.

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

[30]  L. Comai,et al.  Requirements for the Nucleolytic Processing of DNA Ends by the Werner Syndrome Protein-Ku70/80 Complex* , 2001, The Journal of Biological Chemistry.

[31]  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.

[32]  F. Alt,et al.  The cellular response to general and programmed DNA double strand breaks. , 2004, DNA repair.

[33]  M. Lieber,et al.  The Mechanism of Human Nonhomologous DNA End Joining* , 2008, Journal of Biological Chemistry.

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

[35]  G. Iliakis,et al.  Marked dependence on growth state of backup pathways of NHEJ. , 2007, International journal of radiation oncology, biology, physics.

[36]  M. O’Connor,et al.  Targeted cancer therapies based on the inhibition of DNA strand break repair , 2007, Oncogene.

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

[38]  David J. Chen,et al.  Artemis deficiency confers a DNA double-strand break repair defect and Artemis phosphorylation status is altered by DNA damage and cell cycle progression. , 2005, DNA repair.

[39]  Jiri Bartek,et al.  Spatial organization of the mammalian genome surveillance machinery in response to DNA strand breaks , 2006, The Journal of cell biology.

[40]  N. Mailand,et al.  Human Xip1 (C2orf13) Is a Novel Regulator of Cellular Responses to DNA Strand Breaks* , 2007, Journal of Biological Chemistry.

[41]  G. Dianov,et al.  Co-ordination of DNA single strand break repair. , 2007, DNA repair.

[42]  R. Rothstein,et al.  Differential regulation of the cellular response to DNA double-strand breaks in G1. , 2008, Molecular cell.

[43]  O. Hammarsten,et al.  DNA-dependent Protein Kinase Catalytic Subunit STRUCTURAL REQUIREMENTS FOR KINASE ACTIVATION BY DNA ENDS , 2002 .

[44]  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.

[45]  M. Weinfeld,et al.  XRCC1 Stimulates Human Polynucleotide Kinase Activity at Damaged DNA Termini and Accelerates DNA Single-Strand Break Repair , 2001, Cell.

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

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

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

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

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

[51]  K. Meek,et al.  The leucine rich region of DNA-PKcs contributes to its innate DNA affinity , 2005, Nucleic acids research.

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

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

[54]  Qi Ding,et al.  Inhibition of homologous recombination by variants of the catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs). , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[55]  Laurence H Pearl,et al.  Three-dimensional structure and regulation of the DNA-dependent protein kinase catalytic subunit (DNA-PKcs). , 2005, Structure.

[56]  S. Lees-Miller,et al.  Repair of DNA double strand breaks by non-homologous end joining. , 2003, Biochimie.

[57]  P. Calsou,et al.  Involvement of Poly(ADP-ribose) Polymerase-1 and XRCC1/DNA Ligase III in an Alternative Route for DNA Double-strand Breaks Rejoining* , 2004, Journal of Biological Chemistry.

[58]  S. Lees-Miller,et al.  DNA damage-induced activation of ATM and ATM-dependent signaling pathways. , 2004, DNA repair.

[59]  Timothy Woods,et al.  Autophosphorylation of the Catalytic Subunit of the DNA-Dependent Protein Kinase Is Required for Efficient End Processing during DNA Double-Strand Break Repair , 2003, Molecular and Cellular Biology.

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

[61]  D. Chan,et al.  The DNA-dependent Protein Kinase Is Inactivated by Autophosphorylation of the Catalytic Subunit (*) , 1996, The Journal of Biological Chemistry.

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

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

[64]  Shengfang Jin,et al.  Binding of Ku and c-Abl at the Kinase Homology Region of DNA-dependent Protein Kinase Catalytic Subunit* , 1997, The Journal of Biological Chemistry.

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

[66]  Huichen Wang,et al.  DNA ligase III as a candidate component of backup pathways of nonhomologous end joining. , 2005, Cancer research.

[67]  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.

[68]  K. Caldecott,et al.  TDP1 facilitates chromosomal single‐strand break repair in neurons and is neuroprotective in vivo , 2007, The EMBO journal.

[69]  M. Jovanović,et al.  Identification of DNA-PKcs phosphorylation sites in XRCC4 and effects of mutations at these sites on DNA end joining in a cell-free system. , 2004, DNA repair.

[70]  J. Nickoloff,et al.  Regulation of DNA double-strand break repair pathway choice , 2008, Cell Research.

[71]  Robert T Abraham,et al.  PI 3-kinase related kinases: 'big' players in stress-induced signaling pathways. , 2004, DNA repair.

[72]  M. Weinfeld,et al.  Stable down-regulation of human polynucleotide kinase enhances spontaneous mutation frequency and sensitizes cells to genotoxic agents. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[73]  D. Ramsden,et al.  Werner protein cooperates with the XRCC4-DNA ligase IV complex in end-processing. , 2008, Biochemistry.

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

[75]  David J. Chen,et al.  Cell Cycle Dependence of DNA-dependent Protein Kinase Phosphorylation in Response to DNA Double Strand Breaks* , 2005, Journal of Biological Chemistry.

[76]  S. Lees-Miller,et al.  The DNA-dependent protein kinase interacts with DNA to form a protein-DNA complex that is disrupted by phosphorylation. , 2002, Biochemistry.

[77]  Stephen C. West,et al.  Poly(ADP-ribose)-binding zinc finger motifs in DNA repair/checkpoint proteins , 2008, Nature.

[78]  B. A. Ballif,et al.  ATM and ATR Substrate Analysis Reveals Extensive Protein Networks Responsive to DNA Damage , 2007, Science.

[79]  David J. Chen,et al.  Live cell imaging of XLF and XRCC4 reveals a novel view of protein assembly in the non-homologous end-joining pathway , 2008, Cell cycle.

[80]  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.

[81]  G. Tsujimoto,et al.  Differential subcellular localization of DNA-dependent protein kinase components Ku and DNA-PKcs during mitosis. , 1999, Journal of cell science.

[82]  T. Helleday,et al.  DNA double-strand break repair: from mechanistic understanding to cancer treatment. , 2007, DNA repair.

[83]  K. Schwarz,et al.  Flexibility in the order of action and in the enzymology of the nuclease, polymerases, and ligase of vertebrate non-homologous DNA end joining: relevance to cancer, aging, and the immune system , 2008, Cell Research.

[84]  F. Alt,et al.  The XRCC4 gene encodes a novel protein involved in DNA double-strand break repair and V(D)J recombination , 1995, Cell.

[85]  J. Allalunis-Turner,et al.  Human polynucleotide kinase participates in repair of DNA double-strand breaks by nonhomologous end joining but not homologous recombination. , 2007, Cancer research.

[86]  Gilbert Chu,et al.  Processing of DNA for nonhomologous end‐joining by cell‐free extract , 2005, The EMBO journal.

[87]  N. Kleckner,et al.  The ATRs, ATMs, and TORs Are Giant HEAT Repeat Proteins , 2003, Cell.

[88]  S. Lees-Miller,et al.  Autophosphorylation of DNA-Dependent Protein Kinase Regulates DNA End Processing and May Also Alter Double-Strand Break Repair Pathway Choice , 2005, Molecular and Cellular Biology.

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

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

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

[92]  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.

[93]  J. Ménissier-de murcia,et al.  XRCC1 is phosphorylated by DNA-dependent protein kinase in response to DNA damage , 2006, Nucleic acids research.

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

[95]  S. West,et al.  Interplay between human DNA repair proteins at a unique double‐strand break in vivo , 2006, The EMBO journal.

[96]  S. Jackson,et al.  Evolutionary and Functional Conservation of the DNA Non-homologous End-joining Protein, XLF/Cernunnos* , 2006, Journal of Biological Chemistry.

[97]  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.

[98]  P. Jeggo,et al.  ATM and DNA-PK Function Redundantly to Phosphorylate H2AX after Exposure to Ionizing Radiation , 2004, Cancer Research.

[99]  A. Fischer,et al.  Cernunnos, a Novel Nonhomologous End-Joining Factor, Is Mutated in Human Immunodeficiency with Microcephaly , 2006, Cell.

[100]  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.

[101]  Richard Harris,et al.  The 3D solution structure of the C-terminal region of Ku86 (Ku86CTR). , 2004, Journal of molecular biology.

[102]  U. Pannicke,et al.  Length-dependent Binding of Human XLF to DNA and Stimulation of XRCC4·DNA Ligase IV Activity* , 2007, Journal of Biological Chemistry.

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

[104]  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.

[105]  Kai Rothkamm,et al.  Pathways of DNA Double-Strand Break Repair during the Mammalian Cell Cycle , 2003, Molecular and Cellular Biology.

[106]  Jeroen A. A. Demmers,et al.  Dynamic assembly of end-joining complexes requires interaction between Ku70/80 and XRCC4 , 2006, Proceedings of the National Academy of Sciences.

[107]  David J. Chen,et al.  Ku recruits XLF to DNA double‐strand breaks , 2008, EMBO reports.

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

[109]  M. Lieber,et al.  Roles of nonhomologous DNA end joining, V(D)J recombination, and class switch recombination in chromosomal translocations. , 2006, DNA repair.

[110]  K. Sakaguchi,et al.  Human DNA-activated protein kinase phosphorylates serines 15 and 37 in the amino-terminal transactivation domain of human p53 , 1992, Molecular and cellular biology.

[111]  C. Delteil,et al.  Interplay between Ku, Artemis, and the DNA-dependent Protein Kinase Catalytic Subunit at DNA Ends* , 2006, Journal of Biological Chemistry.

[112]  David J. Chen,et al.  Requirement for the Kinase Activity of Human DNA-Dependent Protein Kinase Catalytic Subunit in DNA Strand Break Rejoining , 1999, Molecular and Cellular Biology.

[113]  Phoebe L Stewart,et al.  Cryo-EM structure of the DNA-dependent protein kinase catalytic subunit at subnanometer resolution reveals alpha helices and insight into DNA binding. , 2008, Structure.

[114]  Karen H. Almeida,et al.  A unified view of base excision repair: lesion-dependent protein complexes regulated by post-translational modification. , 2007, DNA repair.

[115]  W. Dynan,et al.  Geometry of a complex formed by double strand break repair proteins at a single DNA end: recruitment of DNA-PKcs induces inward translocation of Ku protein. , 1999, Nucleic acids research.

[116]  R. Legerski,et al.  Artemis Links ATM to G2/M Checkpoint Recovery via Regulation of Cdk1-Cyclin B , 2007, Molecular and Cellular Biology.

[117]  David J. Chen,et al.  Solution structure of the C-terminal domain of Ku80 suggests important sites for protein-protein interactions. , 2004, Structure.

[118]  D. Chan,et al.  Utilization of Oriented Peptide Libraries to Identify Substrate Motifs Selected by ATM* , 2000, The Journal of Biological Chemistry.

[119]  Marco Foiani,et al.  Regulation of DNA repair throughout the cell cycle , 2008, Nature Reviews Molecular Cell Biology.

[120]  M. Lieber,et al.  XRCC4:DNA ligase IV can ligate incompatible DNA ends and can ligate across gaps , 2007, The EMBO journal.

[121]  S. Lees-Miller,et al.  DNA-PK-dependent phosphorylation of Ku70/80 is not required for non-homologous end joining. , 2005, DNA repair.

[122]  Martijn S Luijsterburg,et al.  DNA double-strand breaks are not sufficient to initiate recruitment of TRF2 , 2007, Nature Genetics.

[123]  Stephen P. Jackson,et al.  A means to a DNA end: the many roles of Ku , 2004, Nature Reviews Molecular Cell Biology.

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

[125]  T. Mimori,et al.  DNA-dependent protein kinase (Ku protein-p350 complex) assembles on double-stranded DNA. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[126]  G. Sapkota,et al.  Identification of in vitro and in vivo phosphorylation sites in the catalytic subunit of the DNA-dependent protein kinase. , 2002, The Biochemical journal.

[127]  F. Alt,et al.  Distinct roles of chromatin-associated proteins MDC1 and 53BP1 in mammalian double-strand break repair. , 2007, Molecular cell.

[128]  P. Jeggo,et al.  The life and death of DNA-PK , 2005, Oncogene.

[129]  J. Glover,et al.  Polynucleotide kinase as a potential target for enhancing cytotoxicity by ionizing radiation and topoisomerase I inhibitors. , 2008, Anti-Cancer Agents in Medicinal Chemistry.

[130]  George Iliakis,et al.  Low levels of DNA ligases III and IV sufficient for effective NHEJ , 2007, Journal of cellular physiology.

[131]  N. Curtin,et al.  Preclinical evaluation of a potent novel DNA-dependent protein kinase inhibitor NU7441. , 2006, Cancer research.

[132]  Penny A. Jeggo,et al.  The role of double-strand break repair — insights from human genetics , 2006, Nature Reviews Genetics.

[133]  K. Valerie,et al.  Coordinate 5′ and 3′ endonucleolytic trimming of terminally blocked blunt DNA double-strand break ends by Artemis nuclease and DNA-dependent protein kinase , 2008, Nucleic acids research.

[134]  J. Gautier,et al.  Repair of double-strand breaks by nonhomologous end joining in the absence of Mre11 , 2005, The Journal of cell biology.

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

[136]  S. Jackson,et al.  Mammalian DNA double-strand break repair protein XRCC4 interacts with DNA ligase IV , 1997, Current Biology.

[137]  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.

[138]  J. Nickoloff,et al.  Interactive competition between homologous recombination and non-homologous end joining. , 2003, Molecular cancer research : MCR.

[139]  D. Ramsden,et al.  Sibling rivalry: competition between Pol X family members in V(D)J recombination and general double strand break repair , 2004, Immunological reviews.

[140]  T. Paull.  Saving the ends for last: the role of pol mu in DNA end joining. , 2005, Molecular cell.

[141]  Y. Shiloh.  The ATM-mediated DNA-damage response: taking shape. , 2006, Trends in biochemical sciences.

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

[143]  D. Chan,et al.  DNA-dependent protein kinase phosphorylation sites in Ku 70/80 heterodimer. , 1999, Biochemistry.

[144]  P. Jeggo,et al.  The impact of a negligent G2/M checkpoint on genomic instability and cancer induction , 2007, Nature Reviews Cancer.

[145]  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.

[146]  B. Chen,et al.  ATR-Dependent Phosphorylation of DNA-Dependent Protein Kinase Catalytic Subunit in Response to UV-Induced Replication Stress , 2006, Molecular and Cellular Biology.

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

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

[149]  Qi Ding,et al.  Autophosphorylation-dependent remodeling of the DNA-dependent protein kinase catalytic subunit regulates ligation of DNA ends. , 2004, Nucleic acids research.

[150]  Jiri Bartek,et al.  Cell-cycle checkpoints and cancer , 2004, Nature.

[151]  Yunmei Ma,et al.  The DNA-dependent Protein Kinase Catalytic Subunit Phosphorylation Sites in Human Artemis* , 2005, Journal of Biological Chemistry.

[152]  B. Chait,et al.  Ku80 removal from DNA through double strand break–induced ubiquitylation , 2008, The Journal of cell biology.

[153]  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.

[154]  M. Lavin,et al.  ATM Activation and DNA Damage Response , 2007, Cell cycle.

[155]  Qi Ding,et al.  The DNA-Dependent Protein Kinase Catalytic Subunit Is Phosphorylated In Vivo on Threonine 3950, a Highly Conserved Amino Acid in the Protein Kinase Domain , 2006, Molecular and Cellular Biology.

[156]  D. Ramsden,et al.  The DNA‐dependent protein kinase: the director at the end , 2004, Immunological reviews.

[157]  Steven P Gygi,et al.  Large-scale characterization of HeLa cell nuclear phosphoproteins. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[158]  S. West,et al.  Involvement of human polynucleotide kinase in double‐strand break repair by non‐homologous end joining , 2002, The EMBO journal.

[159]  B. Hemmings,et al.  PKBalpha/Akt1 acts downstream of DNA-PK in the DNA double-strand break response and promotes survival. , 2008, Molecular cell.

[160]  E. Friedberg,et al.  DNA Repair and Mutagenesis , 2006 .

[161]  M. Sadofsky,et al.  SUMO Modification of Human XRCC4 Regulates Its Localization and Function in DNA Double-Strand Break Repair , 2006, Molecular and Cellular Biology.

[162]  Burkhard Jakob,et al.  Autophosphorylation of DNA-PKCS regulates its dynamics at DNA double-strand breaks , 2007, The Journal of cell biology.

[163]  S. Jackson,et al.  gammaH2AX and MDC1: anchoring the DNA-damage-response machinery to broken chromosomes. , 2006, DNA repair.

[164]  T. Kunkel,et al.  Structure-function studies of DNA polymerase lambda. , 2005, DNA repair.

[165]  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.

[166]  David J. Chen,et al.  DNA-dependent protein kinase in nonhomologous end joining: a lock with multiple keys? , 2007, The Journal of cell biology.

[167]  D. Ferguson,et al.  DNA Double-Strand Break Repair: A Relentless Hunt Uncovers New Prey , 2006, Cell.

[168]  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.

[169]  E. Pastwa,et al.  Non-homologous DNA end joining in anticancer therapy. , 2007, Current cancer drug targets.

[170]  K. Meek,et al.  Both V(D)J recombination and radioresistance require DNA-PK kinase activity, though minimal levels suffice for V(D)J recombination. , 2000, Nucleic acids research.

[171]  C. Delteil,et al.  DNA-dependent Protein Kinase and XRCC4-DNA Ligase IV Mobilization in the Cell in Response to DNA Double Strand Breaks* , 2005, Journal of Biological Chemistry.

[172]  M. Mann,et al.  Global, In Vivo, and Site-Specific Phosphorylation Dynamics in Signaling Networks , 2006, Cell.

[173]  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.

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

[175]  L. Povirk.  Biochemical mechanisms of chromosomal translocations resulting from DNA double-strand breaks. , 2006, DNA repair.

[176]  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.

[177]  M. Story,et al.  Artemis Is a Phosphorylation Target of ATM and ATR and Is Involved in the G2/M DNA Damage Checkpoint Response , 2004, Molecular and Cellular Biology.

[178]  Samuel H. Wilson,et al.  The X family portrait: structural insights into biological functions of X family polymerases. , 2007, DNA repair.

[179]  David J. Chen,et al.  Independent and sequential recruitment of NHEJ and HR factors to DNA damage sites in mammalian cells , 2005, The Journal of cell biology.

[180]  T. Morio,et al.  Ataxia‐telangiectasia‐mutated dependent phosphorylation of Artemis in response to DNA damage , 2005, Cancer science.

[181]  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.