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Polh  -  polymerase (DNA directed), eta (RAD 30...

Mus musculus

Synonyms: DNA polymerase eta, RAD30 homolog A, RAD30A, Rad30a, XPV, ...
 
 
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Disease relevance of Polh

  • DNA polymerase eta (Pol eta) is the product of the Polh gene, which is responsible for the group variant of xeroderma pigmentosum, a rare inherited recessive disease which is characterized by susceptibility to sunlight-induced skin cancer [1].
  • Intriguingly, histological diagnosis after chronic treatment with UV light reveals that Pol iota deficiency leads to the formation of mesenchymal tumors, such as sarcomas, that are not observed in Polh(-/-) mice [1].
  • The mutation pattern of immunoglobulin genes was studied in mice deficient for DNA polymerase eta, a translesional polymerase whose inactivation is responsible for the xeroderma pigmentosum variant (XP-V) syndrome in humans [2].
  • Complementation of defective translesion synthesis and UV light sensitivity in xeroderma pigmentosum variant cells by human and mouse DNA polymerase eta [3].
 

High impact information on Polh

  • Mutations at A/T bases within immunoglobulin genes have been shown to be generated by a repair pathway involving the DNA-binding moiety of the mismatch repair complex constituted by the MSH2-MSH6 proteins, together with DNA polymerase eta (pol eta) [4].
  • Similar to their human counterparts, variable and switch regions from Polh-/- mice had fewer substitutions of A.T base pairs and correspondingly more mutations of C.G base pairs, which firmly establishes a central role for pol eta in hypermutation [5].
  • B cells from Polh-/- mice produced normal amounts of IgG, indicating that pol eta does not affect class switch recombination [5].
  • Correlation of somatic hypermutation specificity and A-T base pair substitution errors by DNA polymerase eta during copying of a mouse immunoglobulin kappa light chain transgene [6].
  • While Pol iota deficiency does not influence the UV sensitivity of mouse fibroblasts irrespective of Polh genotype, Polh Poli double-deficient mice show slightly earlier onset of skin tumor formation [1].
 

Chemical compound and disease context of Polh

  • Human DNA polymerase eta (Pol(eta)), encoded by the Xeroderma pigmentosum variant (XPV) gene, is known for its activity of error-free translesion synthesis opposite a TT cis-syn cyclobutane dimer [7].
 

Biological context of Polh

  • We recently reported in a study of Polh mutant mice that Pol eta is involved in the somatic hypermutation of immunoglobulin genes, but the cancer predisposition of Polh(-/-) mice has not been examined until very recently [1].
  • Consistent with the ability of Pol eta to efficiently bypass UV light-induced cyclobutane pyrimidine dimers, XPV cells lacking Pol eta have diminished capacity to replicate UV-damaged DNA and are sensitive to UV light-induced killing and mutagenesis [8].
  • These results suggest that DNA polymerase eta plays a role in DNA replication, though the enzyme is not essential for viability [3].
  • Although the mouse XPV gene was not induced by UV irradiation, its expression was elevated approximately 4-fold during cell proliferation [3].
 

Anatomical context of Polh

  • Northern blot analysis revealed that the mouse XPV gene is expressed ubiquitously, but at a higher level in testis, liver, skin and thymus compared to other tissues [3].
  • Here, we used a spontaneous carcinogenesis model in the skin of DNA polymerase eta-deficient mice and found that interstitial fluid pressure was already elevated in the hyperplastic/dysplastic stage [9].

References

  1. UV-B Radiation Induces Epithelial Tumors in Mice Lacking DNA Polymerase {eta} and Mesenchymal Tumors in Mice Deficient for DNA Polymerase {iota}. Ohkumo, T., Kondo, Y., Yokoi, M., Tsukamoto, T., Yamada, A., Sugimoto, T., Kanao, R., Higashi, Y., Kondoh, H., Tatematsu, M., Masutani, C., Hanaoka, F. Mol. Cell. Biol. (2006) [Pubmed]
  2. Contribution of DNA polymerase eta to immunoglobulin gene hypermutation in the mouse. Delbos, F., De Smet, A., Faili, A., Aoufouchi, S., Weill, J.C., Reynaud, C.A. J. Exp. Med. (2005) [Pubmed]
  3. Complementation of defective translesion synthesis and UV light sensitivity in xeroderma pigmentosum variant cells by human and mouse DNA polymerase eta. Yamada, A., Masutani, C., Iwai, S., Hanaoka, F. Nucleic Acids Res. (2000) [Pubmed]
  4. DNA polymerase {eta} is the sole contributor of A/T modifications during immunoglobulin gene hypermutation in the mouse. Delbos, F., Aoufouchi, S., Faili, A., Weill, J.C., Reynaud, C.A. J. Exp. Med. (2007) [Pubmed]
  5. Different mutation signatures in DNA polymerase eta- and MSH6-deficient mice suggest separate roles in antibody diversification. Martomo, S.A., Yang, W.W., Wersto, R.P., Ohkumo, T., Kondo, Y., Yokoi, M., Masutani, C., Hanaoka, F., Gearhart, P.J. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  6. Correlation of somatic hypermutation specificity and A-T base pair substitution errors by DNA polymerase eta during copying of a mouse immunoglobulin kappa light chain transgene. Pavlov, Y.I., Rogozin, I.B., Galkin, A.P., Aksenova, A.Y., Hanaoka, F., Rada, C., Kunkel, T.A. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  7. Error-prone lesion bypass by human DNA polymerase eta. Zhang, Y., Yuan, F., Wu, X., Rechkoblit, O., Taylor, J.S., Geacintov, N.E., Wang, Z. Nucleic Acids Res. (2000) [Pubmed]
  8. Increased susceptibility to UV-induced skin carcinogenesis in polymerase eta-deficient mice. Lin, Q., Clark, A.B., McCulloch, S.D., Yuan, T., Bronson, R.T., Kunkel, T.A., Kucherlapati, R. Cancer Res. (2006) [Pubmed]
  9. Onset of abnormal blood and lymphatic vessel function and interstitial hypertension in early stages of carcinogenesis. Hagendoorn, J., Tong, R., Fukumura, D., Lin, Q., Lobo, J., Padera, T.P., Xu, L., Kucherlapati, R., Jain, R.K. Cancer Res. (2006) [Pubmed]
 
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