Structural insights into the assembly of human translesion polymerase complexes

Abstract

In addition to DNA repair pathways, cells utilize translesion DNA synthesis (TLS) to bypass DNA lesions during replication. During TLS, Y-family DNA polymerase (Polη, Polκ, Polι and Rev1) inserts specific nucleotide opposite preferred DNA lesions, and then Polζ consisting of two subunits, Rev3 and Rev7, carries out primer extension. Here, we report the complex structures of Rev3-Rev7-Rev1^CTD and Rev3-Rev7-Rev1^CTDPolκ^RIR. These two structures demonstrate that Rev1^CTD contains separate binding sites for Pol- and Rev7. Our BIAcore experiments provide additional support for the notion that the interaction between Rev3 and Rev7 increases the affinity of Rev7 and Rev1. We also verified through FRET experiment that Rev1, Rev3, Rev7 and Polκ form a stable quaternary complex in vivo, thereby suggesting an efficient switching mechanism where the “inserter” polymerase can be immediately replaced by an “extender” polymerase within the same quaternary complex.

Keywords

translesion DNA synthesis / Rev1 / Polκ / Polζ / complex structure

References

[1] Acharya, N., Haracska, L., Johnson, R.E., Unk, I., Prakash, S., and Prakash, L. (2005). Complex formation of yeast Rev1 and Rev7 proteins: a novel role for the polymerase-associated domain. Mol Cell Biol 25, 9734-9740 .10.1128/MCB.25.21.9734-9740.2005
[2] Acharya, N., Johnson, R.E., Prakash, S., and Prakash, L. (2006). Complex formation with Rev1 enhances the proficiency of Saccharomyces cerevisiae DNA polymerase zeta for mismatch extension and for extension opposite from DNA lesions. Mol Cell Biol 26, 9555-9563 .10.1128/MCB.01671-06
[3] Adams, P.D., Afonine, P.V., Bunkoczi, G., Chen, V.B., Davis, I.W., Echols, N., Headd, J.J., Hung, L.-W., Kapral, G.J., Grosse-Kunstleve, R.W., . (2010). PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallographica Section D 66, 213-221 .10.1107/S0907444909052925
[4] Alt, A., Lammens, K., Chiocchini, C., Lammens, A., Pieck, J.C., Kuch, D., Hopfner, K.-P., and Carell, T. (2007). Bypass of DNA lesions generated during anticancer treatment with cisplatin by DNA polymerase η. Science 318, 967-970 .10.1126/science.1148242
[5] Andersen, P.L., Xu, F., Ziola, B., McGregor, W.G., and Xiao, W. (2011). Sequential assembly of translesion DNA polymerases at UV-induced DNA damage sites. Mol Biol Cell 22, 2373-2383 .10.1091/mbc.E10-12-0938
[6] Auerbach, P.A., and Demple, B. (2010). Roles of Rev1, Pol zeta, Pol32 and Pol eta in the bypass of chromosomal abasic sites in Saccharomyces cerevisiae. Mutagenesis 25, 63-69 .10.1093/mutage/gep045
[7] Bienko, M., Green, C.M., Crosetto, N., Rudolf, F., Zapart, G., Coull, B., Kannouche, P., Wider, G., Peter, M., Lehmann, A.R., . (2005). Ubiquitin-binding domains in Y-family polymerases regulate translesion synthesis. Science 310, 1821-1824 .10.1126/science.1120615
[8] Biertü mpfel, C., Z hao, Y., K ondo, Y., Ramón-Maiques, S., Gregory, M., Lee, J.Y., Masutani, C., Lehmann, A.R., Hanaoka, F., and Yang, W. (2010). Structure and mechanism of human DNA polymerase [eegr]. Nature 465, 1044-1048 .10.1038/nature09196
[9] Bomar, M.G., D’Souza, S., Bienko, M., Dikic, I., Walker, G.C., and Zhou, P. (2010). Unconventional ubiquitin recognition by the ubiquitin-binding motif within the Y family DNA polymerases ι and Rev1. Mol Cell 37, 408-417 .10.1016/j.molcel.2009.12.038
[10] Chen, J., Ai, Y., Wang, J., Haracska, L., and Zhuang, Z. (2010). Chemically ubiquitylated PCNA as a probe for eukaryotic translesion DNA synthesis. Nat Chem Biol 6, 270-272 .10.1038/nchembio.316
[11] Chen, Y., Deng, Y., Zhang, J., Yang, L., Xie, X., and Xu, T. (2009). GDI-1 preferably interacts with Rab10 in insulin-stimulated GLUT4 translocation. Biochemical J 422, 229-235 .10.1042/BJ20090624
[12] Collaborative Computational Project, Number 4. (1994). The CCP4 suite: programs for protein crystallography. Acta Crystallogr D Biol Crystallogr 50, 760-763 .10.1107/S0907444994003112
[13] Doles, J., Oliver, T.G., Cameron, E.R., Hsu, G., Jacks, T., Walker, G.C., and Hemann, M.T. (2010). Suppression of Rev3, the catalytic subunit of Polζ, sensitizes drug-resistant lung tumors to chemotherapy. Proc Natl Acad Sci U S A 107, 20786-91 10.1073/pnas.1011409107
[14] Dumstorf, C.A., Mukhopadhyay, S., Krishnan, E., Haribabu, B., and McGregor, W.G. (2009). REV1 is implicated in the development of carcinogen-induced lung cancer. Mol Cancer Res 7, 247-254 .10.1158/1541-7786.MCR-08-0399
[15] Edmunds, C.E., Simpson, L.J., and Sale, J.E. (2008). PCNA ubiquitination and REV1 define temporally distinct mechanisms for controlling translesion synthesis in the avian cell line DT40. Mol Cell 30, 519-529 .10.1016/j.molcel.2008.03.024
[16] Emsley, P., and Cowtan, K. (2004). Coot: model-building tools for molecular graphics. Acta Crystallogr D Biol Crystallogr 60, 2126-2132 .10.1107/S0907444904019158
[17] Freudenthal, B.D., Gakhar, L., Ramaswamy, S., and Washington, M.T. (2010). Structure of monoubiquitinated PCNA and implications for translesion synthesis and DNA polymerase exchange. Nat Struct Mol Biol 17, 479-484 .10.1038/nsmb.1776
[18] Friedberg, E.C., Lehmann, A.R., and Fuchs, R.P.P. (2005). Trading places: how do DNA polymerases switch during translesion DNA synthesis? Mol Cell 18, 499-505 .10.1016/j.molcel.2005.03.032
[19] Gan, G.N., Wittschieben, J.P., Wittschieben, B.O., and Wood, R.D. (2008). DNA polymerase zeta (pol zeta) in higher eukaryotes. Cell Res 18, 174-183 .10.1038/cr.2007.117
[20] Garg, P., Stith, C.M., Majka, J., and Burgers, P.M. (2005). Proliferating cell nuclear antigen promotes translesion synthesis by DNA polymerase zeta. J Biol Chem 280, 23446-23450 .10.1074/jbc.C500173200
[21] Goodman, M.F. (2002). Error-prone repair DNA polymerases in prokaryotes and eukaryotes. Annu Rev Biochem 71, 17-50 .10.1146/annurev.biochem.71.083101.124707
[22] Guo, C., Fischhaber, P.L., Luk-Paszyc, M.J., Masuda, Y., Zhou, J., Kamiya, K., Kisker, C., and Friedberg, E.C. (2003). Mouse Rev1 protein interacts with multiple DNA polymerases involved in translesion DNA synthesis. EMBO J 22, 6621-6630 .10.1093/emboj/cdg626
[23] Guo, C., Kosarek-Stancel, J., Tang, T.-S., and Friedberg, E. (2009). Y-family DNA polymerases in mammalian cells. Cell Mol Life Sci 66, 2363-2381 .10.1007/s00018-009-0024-4
[24] Guo, C., Sonoda, E., Tang, T.-S., Parker, J.L., Bielen, A.B., Takeda, S., Ulrich, H.D., and Friedberg, E.C. (2006). REV1 protein interacts with PCNA: significance of the REV1 BRCT domain in vitro and in vivo. Mol Cell 23, 265-271 .10.1016/j.molcel.2006.05.038
[25] Guo, D., Wu, X., Rajpal, D.K., Taylor, J.S., and Wang, Z. (2001). Translesion synthesis by yeast DNA polymerase zeta from templates containing lesions of ultraviolet radiation and acetylaminofluorene. Nucleic Acids Res 29, 2875-2883 .10.1093/nar/29.13.2875
[26] Hara, K., Hashimoto, H., Murakumo, Y., Kobayashi, S., Kogame, T., Unzai, S., Akashi, S., Takeda, S., Shimizu, T., and Sato, M. (2010). Crystal structure of human REV7 in complex with a human REV3 fragment and structural implication of the interaction between DNA polymerase ζ and REV1. J Biol Chem 285, 12299-12307 .10.1074/jbc.M109.092403
[27] Hoege, C., Pfander, B., Moldovan, G.-L., Pyrowolakis, G., and Jentsch, S. (2002). RAD6-dependent DNA repair is linked to modification of PCNA by ubiquitin and SUMO. Nature 419, 135-141 .10.1038/nature00991
[28] Ito, W., Yokoi, M., Sakayoshi, N., Sakurai, Y., Akagi, J.-i., Mitani, H., and Hanaoka, F. (2012). Stalled Polη at its cognate substrate initiates an alternative translesion synthesis pathway via interaction with REV1. Genes Cells 17, 98-108 .10.1111/j.1365-2443.2011.01576.x
[29] Janda, C.Y., Li, J., Oubridge, C., Hernandez, H., Robinson, C.V., and Nagai, K. (2010). Recognition of a signal peptide by the signal recognition particle. Nature, 465, 507-510 .10.1038/nature08870
[30] Kikuchi, S., Hara, K., Shimizu, T., Sato, M., and Hashimoto, H. (2012). Structural basis of recruitment of DNA polymerase ζ by interaction between REV1 and REV7. J Biol Chem 287, 33847-33852 .10.1074/jbc.M112.396838
[31] Kim, H., Yang, K., Dejsuphong, D., and D’Andrea, A.D. (2012). Regulation of Rev1 by the Fanconi anemia core complex. Nat Struct Mol Biol 19, 164-170 .10.1038/nsmb.2222
[32] Kosarek, J.N., Woodruff, R.V., Rivera-Begeman, A., Guo, C., D’Souza, S., Koonin, E.V., Walker, G.C., and Friedberg, E.C. (2008). Comparative analysis of in vivo interactions between Rev1 protein and other Y-family DNA polymerases in animals and yeasts. DNA Repair 7, 439-451 .10.1016/j.dnarep.2007.11.016
[33] Lawrence, C.W., and Hinkle, D.C. (1996). DNA polymerase zeta and the control of DNA damage induced mutagenesis in eukaryotes. Cancer Surv 28, 21-31 .
[34] Lehmann, A.R., Niimi, A., Ogi, T., Brown, S., Sabbioneda, S., Wing, J.F., Kannouche, P.L., and Green, C.M. (2007). Translesion synthesis: Y-family polymerases and the polymerase switch. DNA Repair 6, 891-899 .10.1016/j.dnarep.2007.02.003
[35] Lin, X., Okuda, T., Trang, J., and Howell, S.B. (2006). Human REV1 modulates the cytotoxicity and mutagenicity of cisplatin in human ovarian carcinoma cells. Mol Pharmacol 69, 1748-1754 .10.1124/mol.105.020446
[36] Livneh, Z., Z, O., and Shachar, S. (2010). Multiple two-polymerase mechanisms in mammalian translesion DNA synthesis. Cell Cycle 9, 729-735 .10.4161/cc.9.4.10727
[37] Mapelli, M., Massimiliano, L., Santaguida, S., and Musacchio, A. (2007). The Mad2 conformational dimer: structure and implications for the spindle assembly checkpoint. Cell 131, 730-743 .10.1016/j.cell.2007.08.049
[38] Masuda, Y., Ohmae, M., Masuda, K., and Kamiya, K. (2003). Structure and enzymatic properties of a stable complex of the human REV1 and REV7 proteins. J Biol Chem 278, 12356-12360 .10.1074/jbc.M211765200
[39] Murakumo, Y., Ogura, Y., Ishii, H., Numata, S., Ichihara, M., Croce, C.M., Fishel, R., and Takahashi, M. (2001). Interactions in the error-prone postreplication repair proteins hREV1, hREV3, and hREV7. J Biol Chem 276, 35644-35651 .10.1074/jbc.M102051200
[40] Murshudov, G.N., Vagin, A.A., and Dodson, E.J. (1997). Refinement of macromolecular structures by the maximum-likelihood method. Acta Crystallogr D Biol Crystallogr 53, 240-255 .10.1107/S0907444996012255
[41] Nair, D.T., Johnson, R.E., Prakash, L., Prakash, S., and Aggarwal, A.K. (2005). Rev1 employs a novel mechanism of DNA synthesis using a protein template. Science 309, 2219-2222 .10.1126/science.1116336
[42] Nair, D.T., Johnson, R.E., Prakash, S., Prakash, L., and Aggarwal, A.K. (2004). Replication by human DNA polymerase-[iota] occurs by Hoogsteen base-pairing. Nature 430, 377-380 .10.1038/nature02692
[43] Ohashi, E., Hanafusa, T., Kamei, K., Song, I., Tomida, J., Hashimoto, H., Vaziri, C., and Ohmori, H. (2009). Identification of a novel REV1-interacting motif necessary for DNA polymerase κ function. Genes Cells 14, 101-111 .10.1111/j.1365-2443.2008.01255.x
[44] Ohashi, E., Murakumo, Y., Kanjo, N., Akagi, J.-i., Masutani, C., Hanaoka, F., and Ohmori, H. (2004). Interaction of hREV1 with three human Y-family DNA polymerases. Genes Cells 9, 523-531 .10.1111/j.1356-9597.2004.00747.x
[45] Okada, T., Sonoda, E., Yoshimura, M., Kawano, Y., Saya, H., Kohzaki, M., and Takeda, S. (2005). Multiple roles of vertebrate REV genes in DNA repair and recombination. Mol Cell Biol 25, 6103-6111 .10.1128/MCB.25.14.6103-6111.2005
[46] Otwinowski, Z., and Minor, W. (1997). Processing of X-ray diffraction data collected in oscillation mode. In (Elsevier), pp. 307-326 .
[47] Plosky, B.S., Vidal, A.E., de Henestrosa, A.R.F., McLenigan, M.P., McDonald, J.P., Mead, S., and Woodgate, R. (2006). Controlling the subcellular localization of DNA polymerases [iota] and [eta] via interactions with ubiquitin. EMBO J 25, 2847-2855 .10.1038/sj.emboj.7601178
[48] Pozhidaeva A, P.Y., D’Souza S, Bezsonova I, Walker GC, Korzhnev DM (2012). NMR structure and dynamics of the C-terminal domain from human Rev1 and its complex with Rev1 interacting region of DNA polymerase η. Biochemistry 51, 5506-5520 .10.1021/bi300566z
[49] Prakash, S., Johnson, R.E., and Prakash, L. (2005). Eukaryotic translesion synthesis DNA polymerases: specificity of structure and function. Annu Rev Biochem 74, 317-353 .10.1146/annurev.biochem.74.082803.133250
[50] R?schle, M., Knipscheer, P., Enoiu, M., Angelov, T., Sun, J., Griffith, J.D., Ellenberger, T.E., Sch?rer, O.D., and Walter, J.C. (2008). Mechanism of replication-coupled DNA interstrand crosslink repair. Cell 134, 969-980 .10.1016/j.cell.2008.08.030
[51] Sale, J.E., Lehmann, A.R., and Woodgate, R. (2012). Y-family DNA polymerases and their role in tolerance of cellular DNA damage. Nat Rev Mol Cell Biol 13, 141-152 .10.1038/nrm3289
[52] Shachar, S., Ziv, O., Avkin, S., Adar, S., Wittschieben, J., Reiszner, T., Chaney, S., Friedberg, E.C., Wang, Z., Carell, T., . (2009). Two-polymerase mechanisms dictate error-free and error-prone translesion DNA synthesis in mammals. EMBO J 28, 383-393 .10.1038/emboj.2008.281
[53] Sharma, S., Hicks, J.K., Chute, C.L., Brennan, J.R., Ahn, J.-Y., Glover, T.W., and Canman, C.E. (2011). REV1 and polymerase ζ facilitate homologous recombination repair. Nucleic Acids Res 40, 682-691 .10.1093/nar/gkr769
[54] Uljon, S.N., Johnson, R.E., Edwards, T.A., Prakash, S., Prakash, L., and Aggarwal, A.K. (2004). Crystal structure of the catalytic core of human DNA polymerase dappa. Structure 12, 1395-1404 .10.1016/j.str.2004.05.011
[55] Wojtaszek, J., Lee, C.J., D’Souza, S., Minesinger, B., Kim, H., D’Andrea, A.D., Walker, G.C., and Zhou, P. (2012a). Structural basis of Rev1-mediated assembly of a quaternary vertebrate translesion polymerase complex consisting of Rev1, heterodimeric Pol ζ and Pol κ. J Biol Chem 287, 33836-33846 .10.1074/jbc.M112.394841
[56] Wojtaszek, J., Liu, J., D’Souza, S., Wang, S., Xue, Y., Walker, G.C., and Zhou, P. (2012b). Multifaceted recognition of vertebrate Rev1 by translesion polymerases ζ and κ. J Biol Chem 287, 26400-26408 .10.1074/jbc.M112.380998
[57] Xie, K., Doles, J., Hemann, M.T., and Walker, G.C. (2010). Error-prone translesion synthesis mediates acquired chemoresistance. Proc Natl Acad Sci U S A 107, 20792-20797 .10.1073/pnas.1011412107
[58] Zhu, F., and Zhang, M. (2003). DNA polymerase zeta: new insight into eukaryotic mutagenesis and mammalian embryonic development. World J Gastroenterol 9, 1165-1169 .