Skip to main content
SpringerLink
Log in

DNA Polymerase η, a Key Protein in Translesion Synthesis in Human Cells

  • Chapter
  • First Online:
Genome Stability and Human Diseases

Part of the book series: Subcellular Biochemistry ((SCBI,volume 50))

Abstract

Genomic DNA is constantly damaged by exposure to exogenous and endogenous agents. Bulky adducts such as UV-induced cyclobutane pyrimidine dimers (CPDs) in the template DNA present a barrier to DNA synthesis by the major eukaryotic replicative polymerases including DNA polymerase δ. Translesion synthesis (TLS) carried out by specialized DNA polymerases is an evolutionarily conserved mechanism of DNA damage tolerance. The Y family of DNA polymerases, including DNA polymerase η (Pol η), the subject of this chapter, play a key role in TLS. Mutations in the human POLH gene encoding Pol η underlie the genetic disease xeroderma pigmentosum variant (XPV), characterized by sun sensitivity, elevated incidence of skin cancer, and at the cellular level, by delayed replication and hypermutability after UV-irradiation. Pol η is a low fidelity enzyme when copying undamaged DNA, but can carry out error-free TLS at sites of UV-induced dithymine CPDs. The active site of Pol η has an open conformation that can accommodate CPDs, as well as cisplatin-induced intrastrand DNA crosslinks. Pol η is recruited to sites of replication arrest in a tightly regulated process through interaction with PCNA. Pol η-deficient cells show strong activation of downstream DNA damage responses including ATR signaling, and accumulate strand breaks as a result of replication fork collapse. Thus, Pol η plays an important role in preventing genome instability after UV- and cisplatin-induced DNA damage. Inhibition of DNA damage tolerance pathways in tumors might also represent an approach to potentiate the effects of DNA damaging agents such as cisplatin.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

ATM:

ataxia-telangiectasia mutated

ATR:

ATM and Rad3-related

ATRIP:

ATR-interacting protein

CPD:

cyclobutane pyrimidine dimer

DDR:

DNA damage response

DNA-PK:

DNA-dependent protein kinase

Pol η:

DNA polymerase eta

RPA:

replication protein A

XPV:

xeroderma pigmentosum variant

References

  • Aabo, K., Adams, M., Adnitt, P., Alberts, D. S., Athanazziou, A., Barley, V., Bell, D. R., Bianchi, U., Bolis, G., Brady, M. F., Brodovsky, H. S., Bruckner, H., Buyse, M., Canetta, R., Chylak, V., Cohen, C. J., Colombo, N., Conte, P. F., Crowther, D., Edmonson, J. H., Gennatas, C., Gilbey, E., Gore, M., Guthrie, D., and Yeap, B. Y. (1998) Chemotherapy in advanced ovarian cancer: four systematic meta-analyses of individual patient data from 37 randomized trials. Advanced Ovarian Cancer Trialists’ Group. Br J Cancer, 78, 1479–1487.

    CAS  PubMed  Google Scholar 

  • Abraham, R. T. (2004) PI 3-kinase related kinases: ‘big’ players in stress-induced signaling pathways. DNA Repair (Amst), 3, 883–887.

    CAS  Google Scholar 

  • Acharya, N., Yoon, J. H., Gali, H., Unk, I., Haracska, L., Johnson, R. E., Hurwitz, J., Prakash, L., and Prakash, S. (2008) Roles of PCNA-binding and ubiquitin-binding domains in human DNA polymerase eta in translesion DNA synthesis. Proc Natl Acad Sci USA, 105, 17724–17729.

    CAS  PubMed  Google Scholar 

  • Albertella, M. R., Green, C. M., Lehmann, A. R., and O’Connor, M. J. (2005a) A role for polymerase eta in the cellular tolerance to cisplatin-induced damage. Cancer Res, 65, 9799–9806.

    CAS  PubMed  Google Scholar 

  • Albertella, M. R., Lau, A., and O’Connor, M. J. (2005b) The overexpression of specialized DNA polymerases in cancer. DNA Repair (Amst), 4, 583–593.

    CAS  Google Scholar 

  • 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 eta. Science, 318, 967–970.

    CAS  PubMed  Google Scholar 

  • Arlett, C. F., Harcourt, S. A., and Broughton, B. C. (1975) The influence of caffeine on cell survival in excision-proficient and excision-deficient xeroderma pigmentosum and normal human cell strains following ultraviolet-light irradiation. Mutat Res, 33, 341–346.

    CAS  PubMed  Google Scholar 

  • Avkin, S., Goldsmith, M., Velasco-Miguel, S., Geacintov, N., Friedberg, E. C., and Livneh, Z. (2004) Quantitative analysis of translesion DNA synthesis across a Benzo[a]pyrene-Guanine adduct in mammalian cells: the role of DNA polymerase kappa. J Biol Chem, 279, 53298–53305.

    CAS  PubMed  Google Scholar 

  • Avkin, S., Sevilya, Z., Toube, L., Geacintov, N., Chaney, S. G., Oren, M., and Livneh, Z. (2006) p53 and p21 regulate error-prone DNA repair to yield a lower mutation load. Mol Cell, 22, 407–413.

    CAS  PubMed  Google Scholar 

  • Bakkenist, C. J. and Kastan, M. B. (2004) Initiating cellular stress responses. Cell, 118, 9–17.

    CAS  PubMed  Google Scholar 

  • Bambara, R. A., Murante, R. S., and Henricksen, L. A. (1997) Enzymes and reactions at the eukaryotic DNA replication fork. J Biol Chem, 272, 4647–4650.

    CAS  PubMed  Google Scholar 

  • Bartek, J., Lukas, J., and Bartkova, J. (2007) DNA damage response as an anti-cancer barrier: damage threshold and the concept of ‘conditional haploinsufficiency’. Cell Cycle, 6, 2344–2347.

    CAS  PubMed  Google Scholar 

  • Bassett, E., King, N. M., Bryant, M. F., Hector, S., Pendyala, L., Chaney, S. G., and Cordeiro-Stone, M. (2004) The role of DNA polymerase eta in translesion synthesis past platinum-DNA adducts in human fibroblasts. Cancer Res, 64, 6469–6475.

    CAS  PubMed  Google Scholar 

  • Bassett, E., Vaisman, A., Havener, J. M., Masutani, C., Hanaoka, F., and Chaney, S. G. (2003) Efficiency of extension of mismatched primer termini across from cisplatin and oxaliplatin adducts by human DNA polymerases beta and eta in vitro. Biochemistry, 42, 14197–14206.

    CAS  PubMed  Google Scholar 

  • Bétous, R., Rey, L., Wang, G., Pillaire, M.-J., Puget, N., Selves, J., Biard, D., Shin-Ya, K., Vasquez, K., Cazaux, C., and Hoffmann, J.-S. (2009) Role of TLS DNA polymerases eta and kappa in processing naturally occurring structured DNA in human cells. Mol Carcinog, 48, 369–378.

    PubMed  Google Scholar 

  • Bienko, M., Green, C. M., Crosetto, N., Rudolf, F., Zapart, G., Coull, B., Kannouche, P., Wider, G., Peter, M., Lehmann, A. R., Hofmann, K., and Dikic, I. (2005) Ubiquitin-binding domains in Y-family polymerases regulate translesion synthesis. Science, 310, 1821–1824.

    CAS  PubMed  Google Scholar 

  • Binz, S. K., Sheehan, A. M., and Wold, M. S. (2004) Replication protein A phosphorylation and the cellular response to DNA damage. DNA Repair (Amst), 3, 1015–1024.

    CAS  Google Scholar 

  • Bomar, M. G., Pai, M. T., Tzeng, S. R., Li, S. S., and Zhou, P. (2007) Structure of the ubiquitin-binding zinc finger domain of human DNA Y-polymerase eta. EMBO Rep, 8, 247–251.

    CAS  PubMed  Google Scholar 

  • Bomgarden, R. D., Lupardus, P. J., Soni, D. V., Yee, M. C., Ford, J. M., and Cimprich, K. A. (2006) Opposing effects of the UV lesion repair protein XPA and UV bypass polymerase eta on ATR checkpoint signaling. EMBO J, 25, 2605–2614.

    CAS  PubMed  Google Scholar 

  • Boyer, J. C., Kaufmann, W. K., Brylawski, B. P., and Cordeiro-Stone, M. (1990) Defective postreplication repair in xeroderma pigmentosum variant fibroblasts. Cancer Res, 50, 2593–2598.

    CAS  PubMed  Google Scholar 

  • Branzei, D. and Foiani, M. (2007) Interplay of replication checkpoints and repair proteins at stalled replication forks. DNA Repair (Amst), 6, 994–1003.

    CAS  Google Scholar 

  • Branzei, D. and Foiani, M. (2008) Regulation of DNA repair throughout the cell cycle. Nat Rev Mol Cell Biol, 9, 297–308.

    CAS  PubMed  Google Scholar 

  • Burgers, P. M., Koonin, E. V., Bruford, E., Blanco, L., Burtis, K. C., Christman, M. F., Copeland, W. C., Friedberg, E. C., Hanaoka, F., Hinkle, D. C., Lawrence, C. W., Nakanishi, M., Ohmori, H., Prakash, L., Prakash, S., Reynaud, C. A., Sugino, A., Todo, T., Wang, Z., Weill, J. C., and Woodgate, R. (2001) Eukaryotic DNA polymerases: proposal for a revised nomenclature. J Biol Chem, 276, 43487–43490.

    CAS  PubMed  Google Scholar 

  • Carty, M. P., Glynn, M., Maher, M., Smith, T., Yao, J., Dixon, K., McCann, J., Rynn, L., and Flanagan, A. (2003) The RAD30 cancer susceptibility gene. Biochem Soc Trans, 31, 252–256.

    CAS  PubMed  Google Scholar 

  • Carty, M. P., Zernik-Kobak, M., McGrath, S., and Dixon, K. (1994) UV light-induced DNA synthesis arrest in HeLa cells is associated with changes in phosphorylation of human single-stranded DNA-binding protein. EMBO J, 13, 2114–2123.

    CAS  PubMed  Google Scholar 

  • Casali, P., Pal, Z., Xu, Z., and Zan, H. (2006) DNA repair in antibody somatic hypermutation. Trends Immunol, 27, 313–321.

    CAS  PubMed  Google Scholar 

  • Ceppi, P., Novello, S., Cambieri, A., Longo, M., Monica, V., Lo Iacono, M., Giaj-Levra, M., Saviozzi, S., Volante, M., Papotti, M., and Scagliotti, G. (2009) Polymerase eta mRNA expression predicts survival of non-small cell lung cancer patients treated with platinum-based chemotherapy. Clin Cancer Res, 15, 1039–1045.

    CAS  PubMed  Google Scholar 

  • Chaney, S. G., Campbell, S. L., Bassett, E., and Wu, Y. (2005) Recognition and processing of cisplatin- and oxaliplatin-DNA adducts. Crit Rev Oncol Hematol, 53, 3–11.

    PubMed  Google Scholar 

  • Chang, D. J. and Cimprich, K. A. (2009) DNA damage tolerance: when it’s OK to make mistakes. Nat Chem Biol, 5, 82–90.

    CAS  PubMed  Google Scholar 

  • Chen, Y. W., Cleaver, J. E., Hanaoka, F., Chang, C. F., and Chou, K. M. (2006) A novel role of DNA polymerase eta in modulating cellular sensitivity to chemotherapeutic agents. Mol Cancer Res, 4, 257–265.

    CAS  PubMed  Google Scholar 

  • Chen, Y. W., Cleaver, J. E., Hatahet, Z., Honkanen, R. E., Chang, J. Y., Yen, Y., and Chou, K. M. (2008) Human DNA polymerase eta activity and translocation is regulated by phosphorylation. Proc Natl Acad Sci USA, 105, 16578–16583.

    CAS  PubMed  Google Scholar 

  • Cimprich, K. A. and Cortez, D. (2008) ATR: an essential regulator of genome integrity. Nat Rev Mol Cell Biol, 9, 616–627.

    CAS  PubMed  Google Scholar 

  • Cleaver, J. (1972) Xeroderma pigmentosum: variants with normal DNA repair and normal sensitivity to ultraviolet light. J Invest Dermatol, 58, 124–128.

    CAS  PubMed  Google Scholar 

  • Cleaver, J. E., Afzal, V., Feeney, L., McDowell, M., Sadinski, W., Volpe, J. P., Busch, D. B., Coleman, D. M., Ziffer, D. W., Yu, Y., Nagasawa, H., and Little, J. B. (1999) Increased ultraviolet sensitivity and chromosomal instability related to P53 function in the xeroderma pigmentosum variant. Cancer Res, 59, 1102–1108.

    CAS  PubMed  Google Scholar 

  • Cleaver, J. E., Bartholomew, J., Char, D., Crowley, E., Feeney, L., and Limoli, C. L. (2002a) Polymerase eta and p53 jointly regulate cell survival, apoptosis and Mre11 recombination during S phase checkpoint arrest after UV irradiation. DNA Repair, 1, 41–57.

    CAS  PubMed  Google Scholar 

  • Cleaver, J. E., Bartholomew, J., Char, D., Crowley, E., Feeney, L., and Limoli, C. L. (2002b) Polymerase eta and p53 jointly regulate cell survival, apoptosis and Mre11 recombination during S phase checkpoint arrest after UV irradiation. DNA Repair (Amst), 1, 41–57.

    CAS  Google Scholar 

  • Cordeiro-Stone, M., Makhov, A. M., Zaritskaya, L. S., and Griffith, J. D. (1999) Analysis of DNA replication forks encountering a pyrimidine dimer in the template to the leading strand. J Mol Biol, 289, 1207–1218.

    CAS  PubMed  Google Scholar 

  • Cordeiro-Stone, M. and Nikolaishvili-Feinberg, N. (2002) Asymmetry of DNA replication and translesion synthesis of UV-induced thymine dimers. Mutat Res, 510, 91–106.

    CAS  PubMed  Google Scholar 

  • Cordeiro-Stone, M., Zaritskaya, L. S., Price, L. K., and Kaufmann, W. K. (1997) Replication fork bypass of a pyrimidine dimer blocking leading strand DNA synthesis. J Biol Chem, 272, 13945–13954.

    CAS  PubMed  Google Scholar 

  • Cruet-Hennequart, S., Coyne, S., Glynn, M. T., Oakley, G. G., and Carty, M. P. (2006) UV-induced RPA phosphorylation is increased in the absence of DNA polymerase eta and requires DNA-PK. DNA Repair (Amst), 5, 491–504.

    CAS  Google Scholar 

  • Cruet-Hennequart, S., Glynn, M. T., Murillo, L. S., Coyne, S., and Carty, M. P. (2008) Enhanced DNA-PK-mediated RPA2 hyperphosphorylation in DNA polymerase eta-deficient human cells treated with cisplatin and oxaliplatin. DNA Repair (Amst), 7, 582–596.

    CAS  Google Scholar 

  • Davies, A. A., Huttner, D., Daigaku, Y., Chen, S., and Ulrich, H. D. (2008) Activation of ubiquitin-dependent DNA damage bypass is mediated by replication protein A. Mol Cell, 29, 625–636.

    CAS  PubMed  Google Scholar 

  • de Feraudy, S., Limoli, C. L., Giedzinski, E., Karentz, D., Marti, T. M., Feeney, L., and Cleaver, J. E. (2007) Pol eta is required for DNA replication during nucleotide deprivation by hydroxyurea. Oncogene, 26, 5713–5721.

    PubMed  Google Scholar 

  • Diaz, M. and Lawrence, C. (2005) An update on the role of translesion synthesis DNA polymerases in Ig hypermutation. Trends Immunol, 26, 215–220.

    CAS  PubMed  Google Scholar 

  • Durocher, D. and Jackson, S. P. (2001) DNA-PK, ATM and ATR as sensors of DNA damage: variations on a theme? Curr Opin Cell Biol, 13, 225–231.

    CAS  PubMed  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • Flanagan, A. M., Rafferty, G., O’Neill, A., Rynne, L., Kelly, J., McCann, J., and Carty, M. P. (2007) The human POLH gene is not mutated, and is expressed in a cohort of patients with basal or squamous cell carcinoma of the skin. Int J Mol Med, 19, 589–596.

    CAS  PubMed  Google Scholar 

  • Friedberg, E. C. (2001) Why do cells have multiple error-prone DNA polymerases? Environ Mol Mutagen, 38, 105–110.

    CAS  PubMed  Google Scholar 

  • Garg, P. and Burgers, P. M. (2005) DNA polymerases that propagate the eukaryotic DNA replication fork. Crit Rev Biochem Mol Biol, 40, 115–128.

    CAS  PubMed  Google Scholar 

  • Gerlach, V. L., Aravind, L., Gotway, G., Schultz, R. A., Koonin, E. V., and Friedberg, E. C. (1999) Human and mouse homologs of Escherichia coli DinB (DNA polymerase IV), members of the UmuC/DinB superfamily. Proc Natl Acad Sci USA, 96, 11922–11927.

    CAS  PubMed  Google Scholar 

  • Glick, E., Chau, J. S., Vigna, K. L., McCulloch, S. D., Adman, E. T., Kunkel, T. A., and Loeb, L. A. (2003) Amino acid substitutions at conserved Tyrosine 52 alter fidelity and bypass efficiency of human DNA polymerase eta. J Biol Chem, 278, 19341–19346.

    CAS  PubMed  Google Scholar 

  • Glick, E., Vigna, K. L., and Loeb, L. A. (2001) Mutations in human DNA polymerase eta motif II alter bypass of DNA lesions. EMBO J, 20, 7303–7312.

    CAS  PubMed  Google Scholar 

  • Glick, E., White, L. M., Elliott, N. A., Berg, D., Kiviat, N. B., and Loeb, L. A. (2006) Mutations in DNA polymerase eta are not detected in squamous cell carcinoma of the skin. Int J Cancer, 119, 2225–2227.

    CAS  PubMed  Google Scholar 

  • Gueranger, Q., Stary, A., Aoufouchi, S., Faili, A., Sarasin, A., Reynaud, C.-A., and Weill, J.-C. (2008) Role of DNA polymerases eta, iota and zeta in UV resistance and UV-induced mutagenesis in a human cell line. DNA Repair (Amst), 7, 1551–1562.

    CAS  Google Scholar 

  • Haracska, L., Johnson, R. E., Unk, I., Phillips, B., Hurwitz, J., Prakash, L., and Prakash, S. (2001a) Physical and functional interactions of human DNA polymerase eta with PCNA. Mol Cell Biol, 21, 7199–7206.

    CAS  PubMed  Google Scholar 

  • Haracska, L., Johnson, R. E., Unk, I., Phillips, B. B., Hurwitz, J., Prakash, L., and Prakash, S. (2001b) Targeting of human DNA polymerase iota to the replication machinery via interaction with PCNA. Proc Natl Acad Sci USA, 98, 14256–14261.

    CAS  PubMed  Google Scholar 

  • Haracska, L., Kondratick, C. M., Unk, I., Prakash, S., and Prakash, L. (2001c) Interaction with PCNA is essential for yeast DNA polymerase eta function. Mol Cell, 8, 407–415.

    CAS  PubMed  Google Scholar 

  • Haracska, L., Prakash, S., and Prakash, L. (2000a) Replication past O(6)-methylguanine by yeast and human DNA polymerase eta. Mol Cell Biol, 20, 8001–8007.

    CAS  PubMed  Google Scholar 

  • Haracska, L., Torres-Ramos, C. A., Johnson, R. E., Prakash, S., and Prakash, L. (2004) Opposing effects of ubiquitin conjugation and SUMO modification of PCNA on replicational bypass of DNA lesions in Saccharomyces cerevisiae. Mol Cell Biol, 24, 4267–4274.

    CAS  PubMed  Google Scholar 

  • Haracska, L., Unk, I., Johnson, R. E., Phillips, B. B., Hurwitz, J., Prakash, L., and Prakash, S. (2002) Stimulation of DNA synthesis activity of human DNA polymerase kappa by PCNA. Mol Cell Biol, 22, 784–791.

    CAS  PubMed  Google Scholar 

  • Haracska, L., Washington, M. T., Prakash, S., and Prakash, L. (2001d) Inefficient bypass of an abasic site by DNA polymerase eta. J Biol Chem, 276, 6861–6866.

    CAS  PubMed  Google Scholar 

  • Haracska, L., Yu, S. L., Johnson, R. E., Prakash, L., and Prakash, S. (2000b) Efficient and accurate replication in the presence of 7,8-dihydro-8-oxoguanine by DNA polymerase eta. Nat Genet, 25, 458–461.

    CAS  PubMed  Google Scholar 

  • Harper, J. W. and Elledge, S. J. (2007) The DNA damage response: ten years after. Mol Cell, 28, 739–745.

    CAS  PubMed  Google Scholar 

  • Hendel, A., Ziv, O., Gueranger, Q., Geacintov, N., and Livneh, Z. (2008) Reduced efficiency and increased mutagenicity of translesion DNA synthesis across a TT cyclobutane pyrimidine dimer, but not a TT 6-4 photoproduct, in human cells lacking DNA polymerase eta. DNA Repair, 7, 1636–1646.

    CAS  PubMed  Google Scholar 

  • Hishida, T., Kubota, Y., Carr, A. M., and Iwasaki, H. (2009) RAD6-RAD18-RAD5-pathway-dependent tolerance to chronic low-dose ultraviolet light. Nature, 457, 612–615.

    CAS  PubMed  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • Huang, T. T., Nijman, S. M. B., Mirchandani, K. D., Galardy, P. J., Cohn, M. A., Haas, W., Gygi, S. P., Ploegh, H. L., Bernards, R., and D’Andrea, A. D. (2006) Regulation of monoubiquitinated PCNA by DUB autocleavage. Nat Cell Biol, 8, 341–347.

    Google Scholar 

  • Indiani, C., McInerney, P., Georgescu, R., Goodman, M. F., and O’Donnell, M. (2005) A sliding-clamp toolbelt binds high- and low-fidelity DNA polymerases simultaneously. Mol Cell, 19, 805–815.

    CAS  PubMed  Google Scholar 

  • Johnson, R. E., Haracska, L., Prakash, S., and Prakash, L. (2001) Role of DNA polymerase zeta in the bypass of a (6-4) TT photoproduct. Mol Cell Biol, 21, 3558–3563.

    CAS  PubMed  Google Scholar 

  • Johnson, R. E., Kondratick, C. M., Prakash, S., and Prakash, L. (1999a) hRAD30 mutations in the variant form of xeroderma pigmentosum. Science, 285, 263–265.

    CAS  PubMed  Google Scholar 

  • Johnson, R. E., Prakash, S., and Prakash, L. (1999b) Efficient bypass of a thymine-thymine dimer by yeast DNA polymerase, Pol-eta. Science, 283, 1001–1004.

    CAS  PubMed  Google Scholar 

  • Johnson, R. E., Trincao, J., Aggarwal, A. K., Prakash, S., and Prakash, L. (2003) Deoxynucleotide triphosphate binding mode conserved in Y family DNA polymerases. Mol Cell Biol, 23, 3008–3012.

    CAS  PubMed  Google Scholar 

  • Kannouche, P., Broughton, B. C., Volker, M., Hanaoka, F., Mullenders, L. H., and Lehmann, A. R. (2001) Domain structure, localization, and function of DNA polymerase eta, defective in xeroderma pigmentosum variant cells. Genes Dev, 15, 158–172.

    CAS  PubMed  Google Scholar 

  • Kannouche, P., Fernandez de Henestrosa, A. R., Coull, B., Vidal, A. E., Gray, C., Zicha, D., Woodgate, R., and Lehmann, A. R. (2003) Localization of DNA polymerases eta and iota to the replication machinery is tightly co-ordinated in human cells. EMBO J, 22, 1223–1233.

    CAS  PubMed  Google Scholar 

  • Kannouche, P. L., Wing, J., and Lehmann, A. R. (2004) Interaction of human DNA polymerase eta with monoubiquitinated PCNA: a possible mechanism for the polymerase switch in response to DNA damage. Mol Cell, 14, 491–500.

    CAS  PubMed  Google Scholar 

  • Kartalou, M. and Essigmann, J. M. (2001) Recognition of cisplatin adducts by cellular proteins. Mutat Res, 478, 1–21.

    CAS  PubMed  Google Scholar 

  • Kawamoto, T., Araki, K., Sonoda, E., Yamashita, Y. M., Harada, K., Kikuchi, K., Masutani, C., Hanaoka, F., Nozaki, K., Hashimoto, N., and Takeda, S. (2005) Dual roles for DNA polymerase eta in homologous DNA recombination and translesion DNA synthesis. Mol Cell, 20, 793–799.

    CAS  PubMed  Google Scholar 

  • Kelland, L. (2007a) Broadening the clinical use of platinum drug-based chemotherapy with new analogues. Satraplatin and picoplatin. Expert Opin Investig Drugs, 16, 1009–1021.

    CAS  PubMed  Google Scholar 

  • Kelland, L. (2007b) The resurgence of platinum-based cancer chemotherapy. Nat Rev Cancer, 7, 573–584.

    CAS  PubMed  Google Scholar 

  • Kelman, Z. and Hurwitz, J. (1998) Protein-PCNA interactions: A DNA-scanning mechanism? Trends Biochem Sci, 23, 236–238.

    CAS  PubMed  Google Scholar 

  • Kim, S.-H. and Michael, W. M. (2008) Regulated proteolysis of DNA polymerase eta during the DNA-damage response in C. elegans. Mol Cell, 32, 757–766.

    CAS  PubMed  Google Scholar 

  • Kondratick, C. M., Washington, M. T., Prakash, S., and Prakash, L. (2001) Acidic residues critical for the activity and biological function of yeast DNA polymerase eta. Mol Cell Biol, 21, 2018–2025.

    CAS  PubMed  Google Scholar 

  • Lawrence, C. W. and Maher, V. M. (2001) Eukaryotic mutagenesis and translesion replication dependent on DNA polymerase zeta and Rev1 protein. Biochem Soc Trans, 29, 187–191.

    CAS  PubMed  Google Scholar 

  • Lehmann, A. R., Kirk-Bell, C. F., Arlett, C. F., Paterson, M. C., Lohman, P. H. M., de Weerd-Kastelein, E. A., and Bootsma, D. (1975) Xeroderma pigmentosum cells with normal levels of excision repair have a defect in DNA synthesis after UV-irradiation. Proc Natl Acad Sci USA, 72, 219–223.

    CAS  PubMed  Google Scholar 

  • 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 (Amst), 6, 891–899.

    CAS  Google Scholar 

  • Limoli, C. L., Giedzinski, E., Bonner, W. M., and Cleaver, J. E. (2002a) UV-induced replication arrest in the xeroderma pigmentosum variant leads to DNA double-strand breaks, gamma-H2AX formation, and Mre11 relocalization. Proc Natl Acad Sci USA, 99, 233–238.

    CAS  PubMed  Google Scholar 

  • Limoli, C. L., Giedzinski, E., and Cleaver, J. E. (2005) Alternative recombination pathways in UV-irradiated XP variant cells. Oncogene, 24, 3708–3714.

    CAS  PubMed  Google Scholar 

  • Limoli, C. L., Giedzinski, E., Morgan, W. F., and Cleaver, J. E. (2000) Inaugural article: polymerase eta deficiency in the xeroderma pigmentosum variant uncovers an overlap between the S phase checkpoint and double-strand break repair. Proc Natl Acad Sci USA, 97, 7939–7946.

    CAS  PubMed  Google Scholar 

  • Limoli, C. L., Laposa, R., and Cleaver, J. E. (2002b) DNA replication arrest in XP variant cells after UV exposure is diverted into an Mre11-dependent recombination pathway by the kinase inhibitor wortmannin. Mutat Res, 510, 121–129.

    CAS  PubMed  Google Scholar 

  • Lin, Q., Clark, A. B., McCulloch, S. D., Yuan, T., Bronson, R. T., Kunkel, T. A., and Kucherlapati, R. (2006) Increased susceptibility to UV-induced skin carcinogenesis in polymerase eta-deficient mice. Cancer Res, 66, 87–94.

    CAS  PubMed  Google Scholar 

  • Ling, H., Boudsocq, F., Woodgate, R., and Yang, W. (2001) Crystal structure of a Y-family DNA polymerase in action: a mechanism for error-prone and lesion-bypass replication. Cell, 107, 91–102.

    CAS  PubMed  Google Scholar 

  • Liu, G. and Chen, X. (2006) DNA polymerase eta, the product of the xeroderma pigmentosum variant gene and a target of p53, modulates the DNA damage checkpoint and p53 activation. Mol Cell Biol, 26, 1398–1413.

    CAS  PubMed  Google Scholar 

  • Liu, V. F. and Weaver, D. T. (1993) The ionizing radiation-induced replication protein A phosphorylation response differs between ataxia telangiectasia and normal human cells. Mol Cell Biol, 13, 7222–7231.

    CAS  PubMed  Google Scholar 

  • Masuda, K., Ouchida, R., Hikida, M., Kurosaki, T., Yokoi, M., Masutani, C., Seki, M., Wood, R. D., Hanaoka, F., and O-Wang, J. (2007) DNA polymerases eta and theta function in the same genetic pathway to generate mutations at A/T during somatic hypermutation of Ig genes. J Biol Chem, 282, 17387–17394.

    CAS  PubMed  Google Scholar 

  • Masutani, C., Araki, M., Yamada, A., Kusumoto, R., Nogimori, T., Maekawa, T., Iwai, S., and Hanaoka, F. (1999a) Xeroderma pigmentosum variant (XP-V) correcting protein from HeLa cells has a thymine dimer bypass DNA polymerase activity. EMBO J, 18, 3491–3501.

    CAS  PubMed  Google Scholar 

  • Masutani, C., Kusumoto, R., Iwai, S., and Hanaoka, F. (2000) Mechanisms of accurate translesion synthesis by human DNA polymerase eta. EMBO J, 19, 3100–3109.

    CAS  PubMed  Google Scholar 

  • Masutani, C., Kusumoto, R., Yamada, A., Dohmae, N., Yokoi, M., Yuasa, M., Araki, M., Iwai, S., Takio, K., and Hanaoka, F. (1999b) The XPV (xeroderma pigmentosum variant) gene encodes human DNA polymerase eta. Nature, 399, 700–704.

    CAS  PubMed  Google Scholar 

  • Matsuoka, S., Ballif, B. A., Smogorzewska, A., McDonald, E. R., III, Hurov, K. E., Luo, J., Bakalarski, C. E., Zhao, Z., Solimini, N., Lerenthal, Y., Shiloh, Y., Gygi, S. P., and Elledge, S. J. (2007) ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science, 316, 1160–1166.

    CAS  PubMed  Google Scholar 

  • McCulloch, S. D., Kokoska, R. J., Masutani, C., Iwai, S., Hanaoka, F., and Kunkel, T. A. (2004) Preferential cis-syn thymine dimer bypass by DNA polymerase eta occurs with biased fidelity. Nature, 428, 97–100.

    CAS  PubMed  Google Scholar 

  • McCulloch, S. D. and Kunkel, T. A. (2008) The fidelity of DNA synthesis by eukaryotic replicative and translesion synthesis polymerases. Cell Res, 18, 148–161.

    CAS  PubMed  Google Scholar 

  • McDonald, J. P., Levine, A. S., and Woodgate, R. (1997) The Saccharomyces cerevisiae RAD30 gene, a homologue of Escherichia coli dinB and umuc, is DNA damage inducible and functions in a novel error-free postreplication repair mechanism. Genetics, 147, 1557–1568.

    CAS  PubMed  Google Scholar 

  • McDonald, J. P., Rapic-Otrin, V., Epstein, J. A., Broughton, B. C., Wang, X., Lehmann, A. R., Wolgemuth, D. J., and Woodgate, R. (1999) Novel human and mouse homologs of Saccharomyces cerevisiae DNA polymerase eta. Genomics, 60, 20–30.

    CAS  PubMed  Google Scholar 

  • McIlwraith, M. J., Vaisman, A., Liu, Y., Fanning, E., Woodgate, R., and West, S. C. (2005) Human DNA polymerase eta promotes DNA synthesis from strand invasion intermediates of homologous recombination. Mol Cell, 20, 783–792.

    CAS  PubMed  Google Scholar 

  • Minko, I. G., Washington, M. T., Kanuri, M., Prakash, L., Prakash, S., and Lloyd, R. S. (2003) Translesion synthesis past acrolein-derived DNA adduct, gamma-hydroxypropanodeoxyguanosine, by yeast and human DNA polymerase eta. J Biol Chem, 278, 784–790.

    CAS  PubMed  Google Scholar 

  • Minko, I. G., Washington, M. T., Prakash, L., Prakash, S., and Lloyd, R. S. (2001) Translesion DNA synthesis by yeast DNA polymerase eta on templates containing N2-Guanine adducts of 1,3-Butadiene metabolites. J Biol Chem, 276, 2517–2522.

    CAS  PubMed  Google Scholar 

  • Nasheuer, H. P., Pospiech, H., and Syväoja, J. (2007) Progress towards the anatomy of the eukaryotic DNA replication fork. In: Lankenau, D. H. (Ed.) Genome Integrity: Facets and Perspectives, Genome Dynamics & Stability, Vol. 1, Springer, Berlin, Heidelberg, New York, pp. 27–68.

    Google Scholar 

  • Nasheuer, H. P., Smith, R., Bauerschmidt, C., Grosse, F., and Weisshart, K. (2002) Initiation of eukaryotic DNA replication: regulation and mechanisms. Prog Nucleic Acid Res Mol Biol, 72, 41–94.

    CAS  PubMed  Google Scholar 

  • Nelson, J. R., Lawrence, C. W., and Hinkle, D. C. (1996) Deoxycytidyl transferase activity of yeast REV1 protein. Nature, 382, 729–731.

    CAS  PubMed  Google Scholar 

  • Oakley, G. G., Loberg, L. I., Yao, J., Risinger, M. A., Yunker, R. L., Zernik-Kobak, M., Khanna, K. K., Lavin, M. F., Carty, M. P., and Dixon, K. (2001) UV-induced hyperphosphorylation of replication protein A depends on DNA replication and expression of ATM protein. Mol Biol Cell, 12, 1199–1213.

    CAS  PubMed  Google Scholar 

  • Oakley, G. G., Patrick, S. M., Yao, J., Carty, M. P., Turchi, J. J., and Dixon, K. (2003) RPA phosphorylation in mitosis alters DNA binding and protein–protein interactions. Biochemistry, 42, 3255–3264.

    CAS  PubMed  Google Scholar 

  • Ogi, T., Kato, T. J., Kato, T., and Ohmori, H. (1999) Mutation enhancement by DINB1, a mammalian homologue of the Escherichia coli mutagenesis protein DinB. Genes Cells, 4, 607–618.

    CAS  PubMed  Google Scholar 

  • Olson, E., Nievera, C. J., Klimovich, V., Fanning, E., and Wu, X. (2006) RPA2 is a direct downstream target for ATR to regulate the S-phase checkpoint. J Biol Chem, 281, 39517–39533.

    CAS  PubMed  Google Scholar 

  • Pan, Q., Fang, Y., Xu, Y., Zhang, K., and Hu, X. (2005) Down-regulation of DNA polymerases kappa, eta, iota, and zeta in human lung, stomach, and colorectal cancers. Cancer Lett, 217, 139–147.

    CAS  PubMed  Google Scholar 

  • Patrick, S. M., Oakley, G. G., Dixon, K., and Turchi, J. J. (2005) DNA damage induced hyperphosphorylation of replication protein A. 2. Characterization of DNA binding activity, protein interactions, and activity in DNA replication and repair. Biochemistry, 44, 8438–8448.

    CAS  PubMed  Google Scholar 

  • Paulsen, R. D. and Cimprich, K. A. (2007) The ATR pathway: fine-tuning the fork. DNA Repair, 6, 953–966.

    CAS  PubMed  Google Scholar 

  • Plosky, B. S., Vidal, A. E., Fernandez de Henestrosa, A. R., 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.

    CAS  PubMed  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • Sarkaria, J. N., Busby, E. C., Tibbetts, R. S., Roos, P., Taya, Y., Karnitz, L. M., and Abraham, R. T. (1999) Inhibition of ATM and ATR kinase activities by the radiosensitizing agent, caffeine. Cancer Res, 59, 4375–4382.

    CAS  PubMed  Google Scholar 

  • Sarkaria, J. N., Tibbetts, R. S., Busby, E. C., Kennedy, A. P., Hill, D. E., and Abraham, R. T. (1998) Inhibition of phosphoinositide 3-kinase related kinases by the radiosensitizing agent wortmannin. Cancer Res, 58, 4375–4382.

    CAS  PubMed  Google Scholar 

  • Shachar, S., Ziv, O., Avkin, S., Adar, S., Wittschieben, J., Reiszner, T., Chaney, S., Friedberg, E. C., Wang, Z., Carell, T., Geacintov, N., and Livneh, Z. (2009) Two-polymerase mechanisms dictate error-free and error-prone translesion DNA synthesis in mammals. EMBO J, 28, 383–393.

    CAS  PubMed  Google Scholar 

  • Shrivastav, M., de Haro, L. P., and Nickoloff, J. A. (2008) Regulation of DNA double-strand break repair pathway choice. Cell Res, 18, 134–147.

    CAS  PubMed  Google Scholar 

  • Skoneczna, A., McIntyre, J., Skoneczny, M., Policinska, Z., and Sledziewska-Gojska, E. (2007) Polymerase eta is a short-lived, proteasomally degraded protein that is temporarily stabilized following UV irradiation in Saccharomyces cerevisiae. J Mol Biol, 366, 1074–1086.

    CAS  PubMed  Google Scholar 

  • Stary, A., Kannouche, P., Lehmann, A. R., and Sarasin, A. (2003) Role of DNA polymerase eta in the UV mutation spectrum in human cells. J Biol Chem, 278, 18767–18775.

    CAS  PubMed  Google Scholar 

  • Stelter, P. and Ulrich, H. D. (2003) Control of spontaneous and damage-induced mutagenesis by SUMO and ubiquitin conjugation. Nature, 425, 188–191.

    CAS  PubMed  Google Scholar 

  • Szuts, D., Marcus, A. P., Himoto, M., Iwai, S., and Sale, J. E. (2008) REV1 restrains DNA polymerase zeta to ensure frame fidelity during translesion synthesis of UV photoproducts in vivo. Nucleic Acids Res, 36, 6767–6780.

    PubMed  Google Scholar 

  • Thakur, M., Wernick, M., Collins, C., Limoli, C. L., Crowley, E., and Cleaver, J. E. (2001) DNA polymerase eta undergoes alternative splicing, protects against UV sensitivity and apoptosis, and suppresses Mre11-dependent recombination. Genes Chromosomes Cancer, 32, 222–235.

    CAS  PubMed  Google Scholar 

  • Trincao, J., Johnson, R. E., Escalante, C. R., Prakash, S., Prakash, L., and Aggarwal, A. K. (2001) Structure of the catalytic core of S. cerevisiae DNA polymerase eta: implications for translesion DNA synthesis. Mol Cell, 8, 417–426.

    CAS  PubMed  Google Scholar 

  • Tung, B. S., McGregor, W. G., Wang, Y. C., Maher, V. M., and McCormick, J. J. (1996) Comparison of the rate of excision of major UV photoproducts in the strands of the human HPRT gene of normal and xeroderma pigmentosum variant cells. Mutat Res, 362, 65–74.

    PubMed  Google Scholar 

  • Vaisman, A., Lehmann, A. R., and Woodgate, R. (2004) DNA polymerases eta and iota. Adv Protein Chem, 69, 205–228.

    CAS  PubMed  Google Scholar 

  • Vaisman, A., Masutani, C., Hanaoka, F., and Chaney, S. G. (2000) Efficient translesion replication past oxaliplatin and cisplatin GpG adducts by human DNA polymerase eta. Biochemistry, 39, 4575–4580.

    CAS  PubMed  Google Scholar 

  • Vreeswijk, M. P., van Hoffen, A., Westland, B. E., Vrieling, H., van Zeeland, A. A., and Mullenders, L. H. (1994) Analysis of repair of cyclobutane pyrimidine dimers and pyrimidine 6-4 pyrimidone photoproducts in transcriptionally active and inactive genes in Chinese hamster cells. J Biol Chem, 269, 31858–31863.

    CAS  PubMed  Google Scholar 

  • Wang, Y., Woodgate, R., McManus, T. P., Mead, S., McCormick, J. J., and Maher, V. M. (2007) Evidence that in xeroderma pigmentosum variant cells, which lack DNA polymerase eta, DNA polymerase iota causes the very high frequency and unique spectrum of UV-induced mutations. Cancer Res, 67, 3018–3026.

    CAS  PubMed  Google Scholar 

  • Wu, X., Yang, Z., Liu, Y., and Zou, Y. (2005) Preferential localization of hyperphosphorylated replication protein A to double-strand break repair and checkpoint complexes upon DNA damage. Biochem J, 391, 473–480.

    CAS  PubMed  Google Scholar 

  • Xiao, Z., Chen, Z., Gunasekera, A. H., Sowin, T. J., Rosenberg, S. H., Fesik, S., and Zhang, H. (2003) Chk1 mediates S and G2 arrests through Cdc25A degradation in response to DNA-damaging agents. J Biol Chem, 278, 21767–21773.

    CAS  PubMed  Google Scholar 

  • Yamada, A., Masutani, C., Iwai, S., and Hanaoka, F. (2000) Complementation of defective translesion synthesis and UV light sensitivity in xeroderma pigmentosum variant cells by human and mouse DNA polymerase eta. Nucleic Acids Res, 28, 2473–2480.

    CAS  PubMed  Google Scholar 

  • Yamada, K., Takezawa, J., and Ezaki, O. (2003) Translesion replication in cisplatin-treated xeroderma pigmentosum variant cells is also caffeine-sensitive: features of the error-prone DNA polymerase(s) involved in UV-mutagenesis. DNA Repair (Amst), 2, 909–924.

    CAS  Google Scholar 

  • Yang, W. and Woodgate, R. (2007) What a difference a decade makes: insights into translesion DNA synthesis. Proc Natl Acad Sci, 104, 15591–15598.

    CAS  PubMed  Google Scholar 

  • Yao, J., Dixon, K., and Carty, M. P. (2001) A single (6-4) photoproduct inhibits plasmid DNA replication in xeroderma pigmentosum variant cell extracts. Environ Mol Mutagen, 38, 19–29.

    CAS  PubMed  Google Scholar 

  • Yuasa, M., Masutani, C., Eki, T., and Hanaoka, F. (2000) Genomic structure, chromosomal localization and identification of mutations in the xeroderma pigmentosum variant (XPV) gene. Oncogene, 19, 4721–4728.

    CAS  PubMed  Google Scholar 

  • Zernik-Kobak, M., Vasunia, K., Connelly, M., Anderson, C. W., and Dixon, K. (1997) Sites of UV-induced phosphorylation of the p34 subunit of replication protein A from HeLa cells. J Biol Chem, 272, 23896–23904.

    CAS  PubMed  Google Scholar 

  • Zhang, Y., Wu, X., Guo, D., Rechkoblit, O., Geacintov, N. E., and Wang, Z. (2002) Two-step error-prone bypass of the (+)- and (–)-trans-anti-BPDE-N2-dG adducts by human DNA polymerases eta and kappa. Mutat Res Fundam Mol Mech Mutagen, 510, 23–35.

    CAS  Google Scholar 

  • Zhou, B. B. and Elledge, S. J. (2000) The DNA damage response: putting checkpoints in perspective. Nature, 408, 433–439.

    CAS  PubMed  Google Scholar 

  • Zhuang, Z., Johnson, R. E., Haracska, L., Prakash, L., Prakash, S., and Benkovic, S. J. (2008) Regulation of polymerase exchange between Pol eta and Pol delta by monoubiquitination of PCNA and the movement of DNA polymerase holoenzyme. Proc Natl Acad Sci USA, 105, 5361–5366.

    CAS  PubMed  Google Scholar 

  • Zou, L. and Elledge, S. J. (2003) Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes. Science, 300, 1542–1548.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Centre for Chromosome Biology, School of Natural Sciences, National University of Ireland, Galway, University Rd, Galway, Ireland

    Séverine Cruet-Hennequart, Kathleen Gallagher & Michael P. Carty

  2. DNA Damage Response Laboratory, Biochemistry, School of Natural Sciences, National University of Ireland, Galway, Galway, Ireland

    Anna M. Sokòl & Sangamitra Villalan

  3. Centre for Chromosome Biology, School of Natural Sciences, National University of Ireland, Galway, Galway, Ireland

    Áine M. Prendergast

Authors
  1. Séverine Cruet-Hennequart
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kathleen Gallagher
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anna M. Sokòl
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sangamitra Villalan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Áine M. Prendergast
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michael P. Carty
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael P. Carty .

Editor information

Editors and Affiliations

  1. Galway, Ireland

    Heinz-Peter Nasheuer

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Springer Science+Business Media B.V.

About this chapter

Cite this chapter

Cruet-Hennequart, S., Gallagher, K., Sokòl, A.M., Villalan, S., Prendergast, Á.M., Carty, M.P. (2010). DNA Polymerase η, a Key Protein in Translesion Synthesis in Human Cells. In: Nasheuer, HP. (eds) Genome Stability and Human Diseases. Subcellular Biochemistry, vol 50. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-3471-7_10

Download citation

Publish with us

Policies and ethics

Search

Navigation