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POLH  -  polymerase (DNA directed), eta

Homo sapiens

Synonyms: DNA polymerase eta, RAD30, RAD30 homolog A, RAD30A, XP-V, ...
 
 
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Disease relevance of POLH

  • Mutation of the POLH gene encoding DNA polymerase eta (pol eta) causes the UV-sensitivity syndrome xeroderma pigmentosum-variant (XP-V) which is linked to the ability of pol eta to accurately bypass UV-induced cyclobutane pyrimidine dimers during a process termed translesion synthesis [1].
  • Here, we tested the hypothesis that somatic mutations and/or polymorphisms in the POLH gene that encodes Poleta are associated with the induction of UV-dependent skin cancers [2].
  • We conclude that neither mutations nor polymorphisms in the coding regions of POLH are required for the generation of human skin squamous cell carcinoma [2].
  • After transformation by HPV16 E7, which targets the retinoblastoma cell cycle regulatory gene, there is no change in the UV sensitivity of XPV cells; but, when transformed by HPV16 E6 or E6 and E7 combined, there is a large increase in UV sensitivity and in the induction of SCEs [3].
  • The majority of the XP melanomas were of the lentigo maligna melanoma (LMM) type, as found in the elderly. p53 point mutations were found in 60% of XP-C melanomas and in only 10% of XPV melanomas, this latter frequency being similar to what has been reported in the general population [4].
 

High impact information on POLH

 

Chemical compound and disease context of POLH

 

Biological context of POLH

 

Anatomical context of POLH

  • Moreover, the UBZ domain of poleta is essential to efficiently restore a normal response to ultraviolet irradiation in xeroderma pigmentosum variant (XP-V) fibroblasts [17].
  • Here it is shown that XP variant (XP-V) cell lines harbor nonsense or frameshift mutations in hRAD30, the human counterpart of yeast RAD30 [18].
  • To determine whether DNA polymerase eta plays a role in the hypermutation of immunoglobulin variable genes, we examined the frequency and pattern of substitutions in variable VH6 genes from the peripheral blood lymphocytes of three patients with xeroderma pigmentosum variant disease, whose polymerase eta had genetic defects [19].
  • Here we show, by analyzing switched memory B cells from two XP-V patients, that pol eta is also an A/T mutator during CSR, in both the switch region of tandem repeats as well as upstream of it, thus suggesting that the same error-prone translesional polymerases are involved, together with AID, in both processes [20].
  • One of the XPV transformed cell lines (CTag) was characterized further as a potential source of cell-free extracts with capability for catalyzing the T antigen-dependent in vitro replication of plasmid DNA carrying the SV40 origin of replication [21].
 

Associations of POLH with chemical compounds

  • Thymine-thymine CPDs, and probably also CPDs containing cytosine, are replicated in vivo in a largely accurate manner by a DNA polymerase eta (Pol eta) dependent process [22].
  • The XPV polymerase activity was dependent on MgCl2, sensitive to NEM, moderately sensitive to KCl, resistant to both aphidicolin and ddTTP, and not stimulated by PCNA [7].
  • After transformation with SV40, XPV cell lines are only slightly UV sensitive, like their primary counterparts, but their sensitization with caffeine and the induction of sister chromatid exchanges (SCEs) by UV irradiation are greatly enhanced [3].
  • Here, we show that independent XP-V cell lines are dramatically more sensitive to cisplatin than the same cells complemented with functional pol eta [1].
  • Mammalian translesion DNA synthesis across an acrolein-derived deoxyguanosine adduct. Participation of DNA polymerase eta in error-prone synthesis in human cells [23].
 

Physical interactions of POLH

  • A human DNA polymerase eta complex containing Rad18, Rad6 and Rev1; proteomic analysis and targeting of the complex to the chromatin-bound fraction of cells undergoing replication fork arrest [24].
 

Other interactions of POLH

 

Analytical, diagnostic and therapeutic context of POLH

  • UVs syndrome is distinct from Cockayne syndrome (CS) or XP including XP variant (XP-V), as determined by studies of genetic factors using cell fusion, microinjection, and postreplication repair assays [28].
  • Using an alkaline sucrose density gradient centrifugation (ASDG) technique, translesion replication is detected in the two XP-V strains XP30RO and XP115LO [29].
  • Twenty-four hours after infection, the DNA polymerase eta-EGFP fusion protein was detected by Western blot analysis, demonstrating successful transduction by the adenoviral vector [30].

References

  1. A role for polymerase eta in the cellular tolerance to cisplatin-induced damage. Albertella, M.R., Green, C.M., Lehmann, A.R., O'Connor, M.J. Cancer Res. (2005) [Pubmed]
  2. Mutations in DNA polymerase eta are not detected in squamous cell carcinoma of the skin. Glick, E., White, L.M., Elliott, N.A., Berg, D., Kiviat, N.B., Loeb, L.A. Int. J. Cancer (2006) [Pubmed]
  3. Increased ultraviolet sensitivity and chromosomal instability related to P53 function in the xeroderma pigmentosum variant. 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., Little, J.B. Cancer Res. (1999) [Pubmed]
  4. Association between DNA repair-deficiency and high level of p53 mutations in melanoma of Xeroderma pigmentosum. Spatz, A., Giglia-Mari, G., Benhamou, S., Sarasin, A. Cancer Res. (2001) [Pubmed]
  5. Low fidelity DNA synthesis by human DNA polymerase-eta. Matsuda, T., Bebenek, K., Masutani, C., Hanaoka, F., Kunkel, T.A. Nature (2000) [Pubmed]
  6. The XPV (xeroderma pigmentosum variant) gene encodes human DNA polymerase eta. Masutani, C., Kusumoto, R., Yamada, A., Dohmae, N., Yokoi, M., Yuasa, M., Araki, M., Iwai, S., Takio, K., Hanaoka, F. Nature (1999) [Pubmed]
  7. Xeroderma pigmentosum variant (XP-V) correcting protein from HeLa cells has a thymine dimer bypass DNA polymerase activity. Masutani, C., Araki, M., Yamada, A., Kusumoto, R., Nogimori, T., Maekawa, T., Iwai, S., Hanaoka, F. EMBO J. (1999) [Pubmed]
  8. The mechanism of nucleotide incorporation by human DNA polymerase eta differs from that of the yeast enzyme. Washington, M.T., Johnson, R.E., Prakash, L., Prakash, S. Mol. Cell. Biol. (2003) [Pubmed]
  9. Role of DNA polymerase zeta in the bypass of a (6-4) TT photoproduct. Johnson, R.E., Haracska, L., Prakash, S., Prakash, L. Mol. Cell. Biol. (2001) [Pubmed]
  10. The role of DNA polymerase eta in translesion synthesis past platinum-DNA adducts in human fibroblasts. Bassett, E., King, N.M., Bryant, M.F., Hector, S., Pendyala, L., Chaney, S.G., Cordeiro-Stone, M. Cancer Res. (2004) [Pubmed]
  11. Cancer protection in xeroderma pigmentosum variant (XP-V). Somos, S., Farkas, B., Schneider, I. Anticancer Res. (1999) [Pubmed]
  12. Nucleotide excision repair- and polymerase eta-mediated error-prone removal of mitomycin C interstrand cross-links. Zheng, H., Wang, X., Warren, A.J., Legerski, R.J., Nairn, R.S., Hamilton, J.W., Li, L. Mol. Cell. Biol. (2003) [Pubmed]
  13. Genome sequence and splice site analysis of low-fidelity DNA polymerases H and I involved in replication of damaged DNA. Cleaver, J.E., Collins, C., Ellis, J., Volik, S. Genomics (2003) [Pubmed]
  14. Sequence context-dependent replication of DNA templates containing UV-induced lesions by human DNA polymerase iota. Vaisman, A., Frank, E.G., Iwai, S., Ohashi, E., Ohmori, H., Hanaoka, F., Woodgate, R. DNA Repair (Amst.) (2003) [Pubmed]
  15. DNA polymerase eta, the product of the xeroderma pigmentosum variant gene and a target of p53, modulates the DNA damage checkpoint and p53 activation. Liu, G., Chen, X. Mol. Cell. Biol. (2006) [Pubmed]
  16. Molecular genetics of Xeroderma pigmentosum variant. Gratchev, A., Strein, P., Utikal, J., Sergij, G. Exp. Dermatol. (2003) [Pubmed]
  17. Ubiquitin-binding domains in Y-family polymerases regulate translesion synthesis. Bienko, M., Green, C.M., Crosetto, N., Rudolf, F., Zapart, G., Coull, B., Kannouche, P., Wider, G., Peter, M., Lehmann, A.R., Hofmann, K., Dikic, I. Science (2005) [Pubmed]
  18. hRAD30 mutations in the variant form of xeroderma pigmentosum. Johnson, R.E., Kondratick, C.M., Prakash, S., Prakash, L. Science (1999) [Pubmed]
  19. DNA polymerase eta is an A-T mutator in somatic hypermutation of immunoglobulin variable genes. Zeng, X., Winter, D.B., Kasmer, C., Kraemer, K.H., Lehmann, A.R., Gearhart, P.J. Nat. Immunol. (2001) [Pubmed]
  20. DNA polymerase eta is involved in hypermutation occurring during immunoglobulin class switch recombination. Faili, A., Aoufouchi, S., Weller, S., Vuillier, F., Stary, A., Sarasin, A., Reynaud, C.A., Weill, J.C. J. Exp. Med. (2004) [Pubmed]
  21. Xeroderma pigmentosum variant: generation and characterization of fibroblastic cell lines transformed with SV40 large T antigen. King, S.A., Wilson, S.J., Farber, R.A., Kaufmann, W.K., Cordeiro-Stone, M. Exp. Cell Res. (1995) [Pubmed]
  22. The role of DNA polymerase iota in UV mutational spectra. Choi, J.H., Besaratinia, A., Lee, D.H., Lee, C.S., Pfeifer, G.P. Mutat. Res. (2006) [Pubmed]
  23. Mammalian translesion DNA synthesis across an acrolein-derived deoxyguanosine adduct. Participation of DNA polymerase eta in error-prone synthesis in human cells. Yang, I.Y., Miller, H., Wang, Z., Frank, E.G., Ohmori, H., Hanaoka, F., Moriya, M. J. Biol. Chem. (2003) [Pubmed]
  24. A human DNA polymerase eta complex containing Rad18, Rad6 and Rev1; proteomic analysis and targeting of the complex to the chromatin-bound fraction of cells undergoing replication fork arrest. Yuasa, M.S., Masutani, C., Hirano, A., Cohn, M.A., Yamaizumi, M., Nakatani, Y., Hanaoka, F. Genes Cells (2006) [Pubmed]
  25. Physical and functional interactions of human DNA polymerase eta with PCNA. Haracska, L., Johnson, R.E., Unk, I., Phillips, B., Hurwitz, J., Prakash, L., Prakash, S. Mol. Cell. Biol. (2001) [Pubmed]
  26. High mobility of flap endonuclease 1 and DNA polymerase eta associated with replication foci in mammalian S-phase nucleus. Solovjeva, L., Svetlova, M., Sasina, L., Tanaka, K., Saijo, M., Nazarov, I., Bradbury, M., Tomilin, N. Mol. Biol. Cell (2005) [Pubmed]
  27. DNA replication arrest in XP variant cells after UV exposure is diverted into an Mre11-dependent recombination pathway by the kinase inhibitor wortmannin. Limoli, C.L., Laposa, R., Cleaver, J.E. Mutat. Res. (2002) [Pubmed]
  28. Clinical characteristics of three patients with UVs syndrome, a photosensitive disorder with defective DNA repair. Itoh, T., Yamaizumi, M., Ichihashi, M., Hiro-Oka, M., Matsui, T., Matsuno, M., Ono, T. Br. J. Dermatol. (1996) [Pubmed]
  29. 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. Yamada, K., Takezawa, J., Ezaki, O. DNA Repair (Amst.) (2003) [Pubmed]
  30. Adenovirus mediated transduction of the human DNA polymerase eta cDNA. Lima-Bessa, K.M., Chiganças, V., Stary, A., Kannouche, P., Sarasin, A., Armelini, M.G., de Fátima Jacysyn, J., Amarante-Mendes, G.P., Cordeiro-Stone, M., Cleaver, J.E., Menck, C.F. DNA Repair (Amst.) (2006) [Pubmed]
 
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