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Structural basis for a novel mechanism of DNA bridging and alignment in eukaryotic DSB DNA repair.

Gouge J, Rosario S, Romain F, Poitevin F, Béguin P, Delarue M
EMBO J 34 1126-42 (2015)
Related entries: 4qz8, 4qz9, 4qza, 4qzb, 4qzc, 4qzd, 4qze, 4qzf, 4qzh, 4qzi

Cited: 16 times
EuropePMC logo PMID: 25762590

Abstract

Eukaryotic DNA polymerase mu of the PolX family can promote the association of the two 3'-protruding ends of a DNA double-strand break (DSB) being repaired (DNA synapsis) even in the absence of the core non-homologous end-joining (NHEJ) machinery. Here, we show that terminal deoxynucleotidyltransferase (TdT), a closely related PolX involved in V(D)J recombination, has the same property. We solved its crystal structure with an annealed DNA synapsis containing one micro-homology (MH) base pair and one nascent base pair. This structure reveals how the N-terminal domain and Loop 1 of Tdt cooperate for bridging the two DNA ends, providing a templating base in trans and limiting the MH search region to only two base pairs. A network of ordered water molecules is proposed to assist the incorporation of any nucleotide independently of the in trans templating base. These data are consistent with a recent model that explains the statistics of sequences synthesized in vivo by Tdt based solely on this dinucleotide step. Site-directed mutagenesis and functional tests suggest that this structural model is also valid for Pol mu during NHEJ.

Articles - 4qzg mentioned but not cited (1)

  1. Structural basis for a novel mechanism of DNA bridging and alignment in eukaryotic DSB DNA repair. Gouge J, Rosario S, Romain F, Poitevin F, Béguin P, Delarue M. EMBO J 34 1126-1142 (2015)


Reviews citing this publication (6)

  1. The molecular basis and disease relevance of non-homologous DNA end joining. Zhao B, Rothenberg E, Ramsden DA, Lieber MR. Nat Rev Mol Cell Biol 21 765-781 (2020)
  2. Translesion and Repair DNA Polymerases: Diverse Structure and Mechanism. Yang W, Gao Y. Annu Rev Biochem 87 239-261 (2018)
  3. Primase-polymerases are a functionally diverse superfamily of replication and repair enzymes. Guilliam TA, Keen BA, Brissett NC, Doherty AJ. Nucleic Acids Res 43 6651-6664 (2015)
  4. Non-homologous end joining: Common interaction sites and exchange of multiple factors in the DNA repair process. Rulten SL, Grundy GJ. Bioessays 39 (2017)
  5. Structure and function relationships in mammalian DNA polymerases. Hoitsma NM, Whitaker AM, Schaich MA, Smith MR, Fairlamb MS, Freudenthal BD. Cell Mol Life Sci 77 35-59 (2020)
  6. Terminal Deoxynucleotidyl Transferase in the Synthesis and Modification of Nucleic Acids. Sarac I, Hollenstein M. Chembiochem 20 860-871 (2019)

Articles citing this publication (9)

  1. Template and primer requirements for DNA Pol θ-mediated end joining. He P, Yang W. Proc Natl Acad Sci U S A 115 7747-7752 (2018)
  2. repgenHMM: a dynamic programming tool to infer the rules of immune receptor generation from sequence data. Elhanati Y, Marcou Q, Mora T, Walczak AM. Bioinformatics 32 1943-1951 (2016)
  3. Structural Basis for a New Templated Activity by Terminal Deoxynucleotidyl Transferase: Implications for V(D)J Recombination. Loc'h J, Rosario S, Delarue M. Structure 24 1452-1463 (2016)
  4. Ku70 suppresses alternative end joining in G1-arrested progenitor B cells. Liang Z, Kumar V, Le Bouteiller M, Zurita J, Kenrick J, Lin SG, Lou J, Hu J, Ye AY, Boboila C, Alt FW, Frock RL. Proc Natl Acad Sci U S A 118 e2103630118 (2021)
  5. Polymerase μ in non-homologous DNA end joining: importance of the order of arrival at a double-strand break in a purified system. Zhao B, Watanabe G, Lieber MR. Nucleic Acids Res 48 3605-3618 (2020)
  6. Enzymatic synthesis of random sequences of RNA and RNA analogues by DNA polymerase theta mutants for the generation of aptamer libraries. Randrianjatovo-Gbalou I, Rosario S, Sismeiro O, Varet H, Legendre R, Coppée JY, Huteau V, Pochet S, Delarue M. Nucleic Acids Res 46 6271-6284 (2018)
  7. Structural evidence for an in trans base selection mechanism involving Loop1 in polymerase μ at an NHEJ double-strand break junction. Loc'h J, Gerodimos CA, Rosario S, Tekpinar M, Lieber MR, Delarue M. J Biol Chem 294 10579-10595 (2019)
  8. Structural snapshots of human DNA polymerase μ engaged on a DNA double-strand break. Kaminski AM, Pryor JM, Ramsden DA, Kunkel TA, Pedersen LC, Bebenek K. Nat Commun 11 4784 (2020)
  9. Polμ tumor variants decrease the efficiency and accuracy of NHEJ. Sastre-Moreno G, Pryor JM, Díaz-Talavera A, Ruiz JF, Ramsden DA, Blanco L. Nucleic Acids Res 45 10018-10031 (2017)


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