DNA polymerase eta explained

DNA polymerase eta (Pol η), is a protein that in humans is encoded by the POLH gene.^{[1] [2] [3]}

DNA polymerase eta is a eukaryotic DNA polymerase involved in the DNA repair by translesion synthesis. The gene encoding DNA polymerase eta is POLH, also known as XPV, because loss of this gene results in the disease xeroderma pigmentosum. Polymerase eta is particularly important for allowing accurate translesion synthesis of DNA damage resulting from ultraviolet radiation or UV.

Function

This gene encodes a member of the Y family of specialized DNA polymerases. It copies undamaged DNA with a lower fidelity than other DNA-directed polymerases. However, it accurately replicates UV-damaged DNA; when thymine dimers are present, this polymerase inserts the complementary nucleotides in the newly synthesized DNA, thereby bypassing the lesion and suppressing the mutagenic effect of UV-induced DNA damage. This polymerase is thought to be involved in hypermutation during immunoglobulin class switch recombination.^[1]

Bypass of 8-oxoguanine

During DNA replication of the Saccharomyces cerevisiae chromosome, the oxidative DNA damage 8-oxoguanine triggers a switch to translesion synthesis by DNA polymerase eta.^[4] This polymerase replicates 8-oxoguanine with an accuracy (insertion of a cytosine opposite the 8-oxoguanine) of approximately 94%. Replication of 8-oxoguanine in the absence of DNA polymerase eta is less than 40%.

Clinical significance

Mutations in this gene result in XPV, a variant type of xeroderma pigmentosum, characterized by sun sensitivity, elevated incidence of skin cancer, and at the cellular level, by delayed replication and hypermutability after UV-irradiation^{[5] [6]}

Interactions

POLH has been shown to interact with PCNA.^[7]

Further reading

• Plachta M, Halas, McIntyre J, Sledziewska-Gojska E . The steady-state level and stability of TLS polymerase eta are cellcycle dependent in the yeast S. cerevisiae . DNA Repair . 29 . 147–153 . 2015 . 10.1016/j.dnarep.2015.02.015 . 25766643 .
• Skoneczna A, McIn Atyre J, Skoneczny M, Policinska Z, Sledziewska-Gojska E . Polymerase eta is a short-lived, proteasomally degraded protein that is temporarily stabilized following UV irradiation in Saccharomyces cerevisiae . J. Mol. Biol. . 366 . 4 . 1074–86 . 2007 . 17198712 . 10.1016/j.jmb.2006.11.093 .
• Masutani C, Kusumoto R, Yamada A, Dohmae N, Yokoi M, Yuasa M, Araki M, Iwai S, Takio K, Hanaoka F . The XPV (xeroderma pigmentosum variant) gene encodes human DNA polymerase eta . Nature . 399 . 6737 . 700–4 . 1999 . 10385124 . 10.1038/21447 . 1999Natur.399..700M . 4429698 .
• Johnson RE, Kondratick CM, Prakash S, Prakash L . hRAD30 mutations in the variant form of xeroderma pigmentosum . Science . 285 . 5425 . 263–5 . 1999 . 10398605 . 10.1126/science.285.5425.263 .
• Masutani C, Kusumoto R, Iwai S, Hanaoka F . Mechanisms of accurate translesion synthesis by human DNA polymerase eta . EMBO J. . 19 . 12 . 3100–9 . 2000 . 10856253 . 203367 . 10.1093/emboj/19.12.3100 .
• Yamada A, Masutani C, Iwai S, Hanaoka F . 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 . 13 . 2473–80 . 2000 . 10871396 . 102698 . 10.1093/nar/28.13.2473 .
• Yuasa M, Masutani C, Eki T, Hanaoka F . Genomic structure, chromosomal localization and identification of mutations in the xeroderma pigmentosum variant (XPV) gene . Oncogene . 19 . 41 . 4721–8 . 2000 . 11032022 . 10.1038/sj.onc.1203842 . free .
• Itoh T, Linn S, Kamide R, Tokushige H, Katori N, Hosaka Y, Yamaizumi M . Xeroderma pigmentosum variant heterozygotes show reduced levels of recovery of replicative DNA synthesis in the presence of caffeine after ultraviolet irradiation . J. Invest. Dermatol. . 115 . 6 . 981–5 . 2000 . 11121129 . 10.1046/j.1523-1747.2000.00154.x . free .
• Zeng X, Winter DB, Kasmer C, Kraemer KH, Lehmann AR, Gearhart PJ . DNA polymerase eta is an A-T mutator in somatic hypermutation of immunoglobulin variable genes . Nat. Immunol. . 2 . 6 . 537–41 . 2001 . 11376341 . 10.1038/88740 . 6213513 .
• Matsuda T, Bebenek K, Masutani C, Rogozin IB, Hanaoka F, Kunkel TA . Error rate and specificity of human and murine DNA polymerase eta . J. Mol. Biol. . 312 . 2 . 335–46 . 2001 . 11554790 . 10.1006/jmbi.2001.4937 .
• Haracska L, Johnson RE, Unk I, Phillips B, Hurwitz J, Prakash L, Prakash S . Physical and functional interactions of human DNA polymerase eta with PCNA . Mol. Cell. Biol. . 21 . 21 . 7199–206 . 2001 . 11585903 . 99895 . 10.1128/MCB.21.21.7199-7206.2001 .
• Glick E, Vigna KL, Loeb LA . Mutations in human DNA polymerase eta motif II alter bypass of DNA lesions . EMBO J. . 20 . 24 . 7303–12 . 2001 . 11743006 . 125802 . 10.1093/emboj/20.24.7303 .
• Limoli CL, Giedzinski E, Bonner WM, Cleaver JE . 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. U.S.A. . 99 . 1 . 233–8 . 2002 . 11756691 . 117544 . 10.1073/pnas.231611798 . 2002PNAS...99..233L . free .
• Broughton BC, Cordonnier A, Kleijer WJ, Jaspers NG, Fawcett H, Raams A, Garritsen VH, Stary A, Avril MF, Boudsocq F, Masutani C, Hanaoka F, Fuchs RP, Sarasin A, Lehmann AR . Molecular analysis of mutations in DNA polymerase eta in xeroderma pigmentosum-variant patients . Proc. Natl. Acad. Sci. U.S.A. . 99 . 2 . 815–20 . 2002 . 11773631 . 117388 . 10.1073/pnas.022473899 . 2002PNAS...99..815B . free .
• Chiapperino D, Kroth H, Kramarczuk IH, Sayer JM, Masutani C, Hanaoka F, Jerina DM, Cheh AM . Preferential misincorporation of purine nucleotides by human DNA polymerase eta opposite benzo[a]pyrene 7,8-diol 9,10-epoxide deoxyguanosine adducts . J. Biol. Chem. . 277 . 14 . 11765–71 . 2002 . 11821420 . 10.1074/jbc.M112139200 . free .
• Kusumoto R, Masutani C, Iwai S, Hanaoka F . Translesion synthesis by human DNA polymerase eta across thymine glycol lesions . Biochemistry . 41 . 19 . 6090–9 . 2002 . 11994004 . 10.1021/bi025549k .
• Yavuz S, Yavuz AS, Kraemer KH, Lipsky PE . The role of polymerase eta in somatic hypermutation determined by analysis of mutations in a patient with xeroderma pigmentosum variant . J. Immunol. . 169 . 7 . 3825–30 . 2002 . 12244178 . 10.4049/jimmunol.169.7.3825 . free .
• Kannouche P, Fernández de Henestrosa AR, Coull B, Vidal AE, Gray C, Zicha D, Woodgate R, Lehmann AR . Localization of DNA polymerases eta and iota to the replication machinery is tightly co-ordinated in human cells . EMBO J. . 21 . 22 . 6246–56 . 2002 . 12426396 . 137208 . 10.1093/emboj/cdf618 .
• Zheng H, Wang X, Warren AJ, Legerski RJ, Nairn RS, Hamilton JW, Li L . Nucleotide excision repair- and polymerase eta-mediated error-prone removal of mitomycin C interstrand cross-links . Mol. Cell. Biol. . 23 . 2 . 754–61 . 2003 . 12509472 . 151552 . 10.1128/MCB.23.2.754-761.2003 .
• Yang IY, Miller H, Wang Z, Frank EG, Ohmori H, Hanaoka F, Moriya M . Mammalian translesion DNA synthesis across an acrolein-derived deoxyguanosine adduct. Participation of DNA polymerase eta in error-prone synthesis in human cells . J. Biol. Chem. . 278 . 16 . 13989–94 . 2003 . 12584190 . 10.1074/jbc.M212535200 . free .
• Kannouche P, Fernández de Henestrosa AR, Coull B, Vidal AE, Gray C, Zicha D, Woodgate R, Lehmann AR . Localization of DNA polymerases eta and iota to the replication machinery is tightly co-ordinated in human cells . EMBO J. . 22 . 5 . 1223–33 . 2003 . 12606586 . 150329 . 10.1093/emboj/cdf618 .

External links

• GeneReviews/NIH/NCBI/UW entry on Xeroderma Pigmentosum

Notes and References

1. Web site: Entrez Gene: POLH polymerase (DNA directed), eta.
2. Masutani C, Kusumoto R, Yamada A, Dohmae N, Yokoi M, Yuasa M, Araki M, Iwai S, Takio K, Hanaoka F . The XPV (xeroderma pigmentosum variant) gene encodes human DNA polymerase eta . Nature . 399 . 6737 . 700–4 . June 1999 . 10385124 . 10.1038/21447 . 1999Natur.399..700M . 4429698 .
3. Johnson RE, Kondratick CM, Prakash S, Prakash L . hRAD30 mutations in the variant form of xeroderma pigmentosum . Science . 285 . 5425 . 263–5 . July 1999 . 10398605 . 10.1126/science.285.5425.263 .
4. Rodriguez GP, Song JB, Crouse GF . In vivo bypass of 8-oxodG . PLOS Genet. . 9 . 8 . e1003682 . 2013 . 23935538 . 3731214 . 10.1371/journal.pgen.1003682 . free .
5. Stary A, Sarasin A . Molecular mechanisms of UV-induced mutations as revealed by the study of DNA polymerase eta in human cells . Res. Microbiol. . 153 . 7 . 441–5 . September 2002 . 12405351 . 10.1016/S0923-2508(02)01343-8 .
6. Book: Cruet-Hennequart S, Gallagher K, Sokòl AM, Villalan S, Prendergast AM, Carty MP . Genome Stability and Human Diseases . DNA Polymerase η, a Key Protein in Translesion Synthesis in Human Cells . 50 . 189–209 . 2010 . 20012583 . 10.1007/978-90-481-3471-7_10 . Subcellular Biochemistry . 978-90-481-3470-0 .
7. Haracska L, Johnson RE, Unk I, Phillips B, Hurwitz J, Prakash L, Prakash S . Physical and functional interactions of human DNA polymerase eta with PCNA . Mol. Cell. Biol. . 21 . 21 . 7199–206 . November 2001 . 11585903 . 99895 . 10.1128/MCB.21.21.7199-7206.2001 .