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Structural insights into the role of domain flexibility in human DNA ligase IV.

Ochi T, Wu Q, Chirgadze DY, Grossmann JG, Bolanos-Garcia VM, Blundell TL
Structure 20 1212-22 (2012)
Cited: 31 times
EuropePMC logo PMID: 22658747

Abstract

Knowledge of the architecture of DNA ligase IV (LigIV) and interactions with XRCC4 and XLF-Cernunnos is necessary for understanding its role in the ligation of double-strand breaks during nonhomologous end joining. Here we report the structure of a subdomain of the nucleotidyltrasferase domain of human LigIV and provide insights into the residues associated with LIG4 syndrome. We use this structural information together with the known structures of the BRCT/XRCC4 complex and those of LigIV orthologs to interpret small-angle X-ray scattering of LigIV in complex with XRCC4 and size exclusion chromatography of LigIV, XRCC4, and XLF-Cernunnos. Our results suggest that the flexibility of the catalytic region is limited in a manner that affects the formation of the LigIV/XRCC4/XLF-Cernunnos complex.

Reviews - 3vnn mentioned but not cited (1)

  1. Repair of double-strand breaks by end joining. Chiruvella KK, Liang Z, Wilson TE. Cold Spring Harb Perspect Biol 5 a012757 (2013)

Articles - 3vnn mentioned but not cited (1)

  1. The dipeptidyl peptidase IV inhibitors vildagliptin and K-579 inhibit a phospholipase C: a case of promiscuous scaffolds in proteins. Chakraborty S, Rendón-Ramírez A, Ásgeirsson B, Dutta M, Ghosh AS, Oda M, Venkatramani R, Rao BJ, Dandekar AM, Goñi FM. F1000Res 2 286 (2013)


Reviews citing this publication (9)

  1. DNA-PK: a dynamic enzyme in a versatile DSB repair pathway. Davis AJ, Chen BP, Chen DJ. DNA Repair (Amst) 17 21-29 (2014)
  2. Detection and repair of ionizing radiation-induced DNA double strand breaks: new developments in nonhomologous end joining. Wang C, Lees-Miller SP. Int J Radiat Oncol Biol Phys 86 440-449 (2013)
  3. Structural insights into NHEJ: building up an integrated picture of the dynamic DSB repair super complex, one component and interaction at a time. Williams GJ, Hammel M, Radhakrishnan SK, Ramsden D, Lees-Miller SP, Tainer JA. DNA Repair (Amst) 17 110-120 (2014)
  4. Protein modeling: what happened to the "protein structure gap"? Schwede T. Structure 21 1531-1540 (2013)
  5. Repair of DNA Double-Strand Breaks by the Nonhomologous End Joining Pathway. Stinson BM, Loparo JJ. Annu Rev Biochem 90 137-164 (2021)
  6. X-ray scattering reveals disordered linkers and dynamic interfaces in complexes and mechanisms for DNA double-strand break repair impacting cell and cancer biology. Hammel M, Tainer JA. Protein Sci 30 1735-1756 (2021)
  7. Human DNA ligases: a comprehensive new look for cancer therapy. Singh DK, Krishna S, Chandra S, Shameem M, Deshmukh AL, Banerjee D. Med Res Rev 34 567-595 (2014)
  8. Structural insights into the role of DNA-PK as a master regulator in NHEJ. Chen S, Lees-Miller JP, He Y, Lees-Miller SP. Genome Instab Dis 2 195-210 (2021)
  9. How to fix DNA breaks: new insights into the mechanism of non-homologous end joining. Vogt A, He Y, Lees-Miller SP. Biochem Soc Trans 51 1789-1800 (2023)

Articles citing this publication (20)

  1. Organization and dynamics of the nonhomologous end-joining machinery during DNA double-strand break repair. Reid DA, Keegan S, Leo-Macias A, Watanabe G, Strande NT, Chang HH, Oksuz BA, Fenyo D, Lieber MR, Ramsden DA, Rothenberg E. Proc Natl Acad Sci U S A 112 E2575-84 (2015)
  2. The fidelity of the ligation step determines how ends are resolved during nonhomologous end joining. Waters CA, Strande NT, Pryor JM, Strom CN, Mieczkowski P, Burkhalter MD, Oh S, Qaqish BF, Moore DT, Hendrickson EA, Ramsden DA. Nat Commun 5 4286 (2014)
  3. Dissection of DNA double-strand-break repair using novel single-molecule forceps. Wang JL, Duboc C, Wu Q, Ochi T, Liang S, Tsutakawa SE, Lees-Miller SP, Nadal M, Tainer JA, Blundell TL, Strick TR. Nat Struct Mol Biol 25 482-487 (2018)
  4. The spatial organization of non-homologous end joining: from bridging to end joining. Ochi T, Wu Q, Blundell TL. DNA Repair (Amst) 17 98-109 (2014)
  5. An Intrinsically Disordered APLF Links Ku, DNA-PKcs, and XRCC4-DNA Ligase IV in an Extended Flexible Non-homologous End Joining Complex. Hammel M, Yu Y, Radhakrishnan SK, Chokshi C, Tsai MS, Matsumoto Y, Kuzdovich M, Remesh SG, Fang S, Tomkinson AE, Lees-Miller SP, Tainer JA. J Biol Chem 291 26987-27006 (2016)
  6. Structure of the catalytic region of DNA ligase IV in complex with an Artemis fragment sheds light on double-strand break repair. Ochi T, Gu X, Blundell TL. Structure 21 672-679 (2013)
  7. DNA Ligase IV Guides End-Processing Choice during Nonhomologous End Joining. Conlin MP, Reid DA, Small GW, Chang HH, Watanabe G, Lieber MR, Ramsden DA, Rothenberg E. Cell Rep 20 2810-2819 (2017)
  8. A single XLF dimer bridges DNA ends during nonhomologous end joining. Graham TGW, Carney SM, Walter JC, Loparo JJ. Nat Struct Mol Biol 25 877-884 (2018)
  9. Structural basis of DNA ligase IV-Artemis interaction in nonhomologous end-joining. De Ioannes P, Malu S, Cortes P, Aggarwal AK. Cell Rep 2 1505-1512 (2012)
  10. XLF acts as a flexible connector during non-homologous end joining. Carney SM, Moreno AT, Piatt SC, Cisneros-Aguirre M, Lopezcolorado FW, Stark JM, Loparo JJ. Elife 9 e61920 (2020)
  11. H2AX facilitates classical non-homologous end joining at the expense of limited nucleotide loss at repair junctions. Feng YL, Xiang JF, Liu SC, Guo T, Yan GF, Feng Y, Kong N, Li HD, Huang Y, Lin H, Cai XJ, Xie AY. Nucleic Acids Res 45 10614-10633 (2017)
  12. Resolution of complex ends by Nonhomologous end joining - better to be lucky than good? Strande NT, Waters CA, Ramsden DA. Genome Integr 3 10 (2012)
  13. The ligation of pol β mismatch insertion products governs the formation of promutagenic base excision DNA repair intermediates. Çağlayan M. Nucleic Acids Res 48 3708-3721 (2020)
  14. DNA ligase I fidelity mediates the mutagenic ligation of pol β oxidized and mismatch nucleotide insertion products in base excision repair. Kamble P, Hall K, Chandak M, Tang Q, Çağlayan M. J Biol Chem 296 100427 (2021)
  15. Stages, scaffolds and strings in the spatial organisation of non-homologous end joining: Insights from X-ray diffraction and Cryo-EM. Liang S, Chaplin AK, Stavridi AK, Appleby R, Hnizda A, Blundell TL. Prog Biophys Mol Biol 163 60-73 (2021)
  16. DNA-PKcs, Allostery, and DNA Double-Strand Break Repair: Defining the Structure and Setting the Stage. Chirgadze DY, Ascher DB, Blundell TL, Sibanda BL. Methods Enzymol 592 145-157 (2017)
  17. Intrinsic protein disorder could be overlooked in cocrystallization conditions: An SRCD case study. Németh E, Balogh RK, Borsos K, Czene A, Thulstrup PW, Gyurcsik B. Protein Sci 25 1977-1988 (2016)
  18. Yeast DNA ligase IV mutations reveal a nonhomologous end joining function of BRCT1 distinct from XRCC4/Lif1 binding. Chiruvella KK, Renard BM, Birkeland SR, Sunder S, Liang Z, Wilson TE. DNA Repair (Amst) 24 37-45 (2014)
  19. Proximal binding of dCas9 at a DNA double strand break stimulates homology-directed repair as a local inhibitor of classical non-homologous end joining. Feng YL, Liu SC, Chen RD, Sun XN, Xiao JJ, Xiang JF, Xie AY. Nucleic Acids Res 51 2740-2758 (2023)
  20. XSuLT: a web server for structural annotation and representation of sequence-structure alignments. Ochoa-Montaño B, Blundell TL. Nucleic Acids Res 45 W381-W387 (2017)


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