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Structural basis of Rev1-mediated assembly of a quaternary vertebrate translesion polymerase complex consisting of Rev1, heterodimeric polymerase (Pol) ζ, and Pol κ.

Wojtaszek J, Lee CJ, D'Souza S, Minesinger B, Kim H, D'Andrea AD, Walker GC, Zhou P
J Biol Chem 287 33836-46 (2012)
Cited: 83 times
EuropePMC logo PMID: 22859295

Abstract

DNA synthesis across lesions during genomic replication requires concerted actions of specialized DNA polymerases in a potentially mutagenic process known as translesion synthesis. Current models suggest that translesion synthesis in mammalian cells is achieved in two sequential steps, with a Y-family DNA polymerase (κ, η, ι, or Rev1) inserting a nucleotide opposite the lesion and with the heterodimeric B-family polymerase ζ, consisting of the catalytic Rev3 subunit and the accessory Rev7 subunit, replacing the insertion polymerase to carry out primer extension past the lesion. Effective translesion synthesis in vertebrates requires the scaffolding function of the C-terminal domain (CTD) of Rev1 that interacts with the Rev1-interacting region of polymerases κ, η, and ι and with the Rev7 subunit of polymerase ζ. We report the purification and structure determination of a quaternary translesion polymerase complex consisting of the Rev1 CTD, the heterodimeric Pol ζ complex, and the Pol κ Rev1-interacting region. Yeast two-hybrid assays were employed to identify important interface residues of the translesion polymerase complex. The structural elucidation of such a quaternary translesion polymerase complex encompassing both insertion and extension polymerases bridged by the Rev1 CTD provides the first molecular explanation of the essential scaffolding function of Rev1 and highlights the Rev1 CTD as a promising target for developing novel cancer therapeutics to suppress translesion synthesis. Our studies support the notion that vertebrate insertion and extension polymerases could structurally cooperate within a megatranslesion polymerase complex (translesionsome) nucleated by Rev1 to achieve efficient lesion bypass without incurring an additional switching mechanism.

Reviews - 4fjo mentioned but not cited (8)

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Articles - 4fjo mentioned but not cited (8)

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  3. Structural basis of Rev1-mediated assembly of a quaternary vertebrate translesion polymerase complex consisting of Rev1, heterodimeric polymerase (Pol) ζ, and Pol κ. Wojtaszek J, Lee CJ, D'Souza S, Minesinger B, Kim H, D'Andrea AD, Walker GC, Zhou P. J Biol Chem 287 33836-33846 (2012)
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  14. Contributions of the specialised DNA polymerases to replication of structured DNA. Wickramasinghe CM, Arzouk H, Frey A, Maiter A, Sale JE. DNA Repair (Amst) 29 83-90 (2015)
  15. Translesion DNA Synthesis in Cancer: Molecular Mechanisms and Therapeutic Opportunities. Zafar MK, Eoff RL. Chem Res Toxicol 30 1942-1955 (2017)
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Articles citing this publication (45)

  1. Human Pol ζ purified with accessory subunits is active in translesion DNA synthesis and complements Pol η in cisplatin bypass. Lee YS, Gregory MT, Yang W. Proc Natl Acad Sci U S A 111 2954-2959 (2014)
  2. A small molecule inhibitor of monoubiquitinated Proliferating Cell Nuclear Antigen (PCNA) inhibits repair of interstrand DNA cross-link, enhances DNA double strand break, and sensitizes cancer cells to cisplatin. Inoue A, Kikuchi S, Hishiki A, Shao Y, Heath R, Evison BJ, Actis M, Canman CE, Hashimoto H, Fujii N. J Biol Chem 289 7109-7120 (2014)
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  4. Interaction between the Rev1 C-Terminal Domain and the PolD3 Subunit of Polζ Suggests a Mechanism of Polymerase Exchange upon Rev1/Polζ-Dependent Translesion Synthesis. Pustovalova Y, Magalhães MT, D'Souza S, Rizzo AA, Korza G, Walker GC, Korzhnev DM. Biochemistry 55 2043-2053 (2016)
  5. Rev7 dimerization is important for assembly and function of the Rev1/Polζ translesion synthesis complex. Rizzo AA, Vassel FM, Chatterjee N, D'Souza S, Li Y, Hao B, Hemann MT, Walker GC, Korzhnev DM. Proc Natl Acad Sci U S A 115 E8191-E8200 (2018)
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  20. Identification of the first small-molecule inhibitor of the REV7 DNA repair protein interaction. Actis ML, Ambaye ND, Evison BJ, Shao Y, Vanarotti M, Inoue A, McDonald ET, Kikuchi S, Heath R, Hara K, Hashimoto H, Fujii N. Bioorg Med Chem 24 4339-4346 (2016)
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  24. In vivo evidence that DNA polymerase kappa is responsible for error-free bypass across DNA cross-links induced by mitomycin C. Takeiri A, Wada NA, Motoyama S, Matsuzaki K, Tateishi H, Matsumoto K, Niimi N, Sassa A, Grúz P, Masumura K, Yamada M, Mishima M, Jishage KI, Nohmi T. DNA Repair (Amst) 24 113-121 (2014)
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  26. REV7 has a dynamic adaptor region to accommodate small GTPase RAN/Shigella IpaB ligands, and its activity is regulated by the RanGTP/GDP switch. Wang X, Pernicone N, Pertz L, Hua D, Zhang T, Listovsky T, Xie W. J Biol Chem 294 15733-15742 (2019)
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  36. Limited ability of DNA polymerase kappa to suppress benzo[a]pyrene-induced genotoxicity in vivo. Masumura K, Toyoda-Hokaiwado N, Niimi N, Grúz P, Wada NA, Takeiri A, Jishage KI, Mishima M, Nohmi T. Environ Mol Mutagen 58 644-653 (2017)
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  38. Structural Basis for the Interaction of Mutasome Assembly Factor REV1 with Ubiquitin. Cui G, Botuyan MV, Mer G. J Mol Biol 430 2042-2050 (2018)
  39. A stapled POL κ peptide targets REV1 to inhibit mutagenic translesion synthesis. Chatterjee N, D'Souza S, Shabab M, Harris CA, Hilinski GJ, Verdine GL, Walker GC. Environ Mol Mutagen 61 830-836 (2020)
  40. Proficient Replication of the Yeast Genome by a Viral DNA Polymerase. Stodola JL, Stith CM, Burgers PM. J Biol Chem 291 11698-11705 (2016)
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