A novel POLH mutation causes XP‑V disease and XP‑V tumor proneness may involve imbalance of numerous DNA polymerases

Guo,Jia; Zhou,Guilan; Zhang,Wenfeng; Song,Yaling; Bian,Zhuan

doi:10.3892/ol.2013.1604

A novel POLH mutation causes XP‑V disease and XP‑V tumor proneness may involve imbalance of numerous DNA polymerases

Authors:
- Jia Guo
- Guilan Zhou
- Wenfeng Zhang
- Yaling Song
- Zhuan Bian
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Affiliations: State Key Laboratory Breeding Base of Basic Science of Stomatology and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, Hubei 430079, P.R. China, Department of Endocrinology, Renmin Hospital of Wuhan University, Wuhan, Hebei 430060, P.R. China
Published online on: October 7, 2013 https://doi.org/10.3892/ol.2013.1604
Pages: 1583-1590

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Abstract

Xeroderma pigmentosum variant (XP‑V) is a subtype of xeroderma pigmentosum (XP) disease with typical pigmentation and types of cancer in the oral maxillofacial and other sun‑exposed regions. Few factors of tumor proneness in XP‑V have been completely elucidated with the exception of the POLH [which encodes DNA polymerase η (pol η)] mutation. The aim of the present study was to identify the POLH mutation in an XP‑V patient and to explore the roles of specific additional polymerases in XP‑V tumor proneness. The POLH gene was sequenced in the patient and the expression of pol η, ι, κ, θ and ζ was tested in XP‑V tumor cells and cell lines, as well as in HeLa cells with POLH knockdown. The results revealed a novel, large homozygous deletion of POLH (del exon 5‑9) in the patient. Lower expression of pol κ, θ and ζ were observed in the XP‑V cells and similar changes were observed in HeLa cells with POLH knockdown. Consistent with XP‑V tumor cells, following UV irradiation, the expression of pol κ and θ presented was significantly increased in the XP‑V cell lines compared with that in the normal control cells. The unusual expression of other polymerases, besides pol η, identified in the present study indicated that these polymerases may also be key in XP‑V cells genetic instability, which accelerates tumor formation.

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1	Kraemer KH, Lee MM and Scotto J: Xeroderma pigmentosum. Cutaneous, ocular and neurologic abnormalities in 830 published cases. Arch Dermatol. 123:241–250. 1987. View Article : Google Scholar : PubMed/NCBI
2	Lehmann AR, McGibbon D and Stefanini M: Xeroderma pigmentosum. Orphanet J Rare Dis. 6:702011. View Article : Google Scholar : PubMed/NCBI
3	Kraemer KH and DiGiovanna JJ: Xeroderma Pigmentosum. GeneReviews. Pagon RA, Bird TD, Dolan CR and Stephens K: Seattle, WA: pp. 1993–2013. 2003
4	Masutani C, Kusumoto R, Yamada A, et al: The XPV (xeroderma pigmentosum variant) gene encodes human DNA polymerase eta. Nature. 399:700–704. 1999. View Article : Google Scholar : PubMed/NCBI
5	Johnson RE, Kondratick CM, Prakash S and Prakash L: hRAD30 mutations in the variant form of xeroderma pigmentosum. Science. 285:263–265. 1999. View Article : Google Scholar : PubMed/NCBI
6	Inui H, Oh KS, Nadem C, et al: Xeroderma pigmentosum-variant patients from America, Europe and Asia. J Invest Dermatol. 128:2055–2068. 2008. View Article : Google Scholar : PubMed/NCBI
7	Gratchev A, Strein P, Utikal J and Sergij G: Molecular genetics of Xeroderma pigmentosum variant. Exp Dermatol. 12:529–536. 2003. View Article : Google Scholar : PubMed/NCBI
8	Broughton BC, Cordonnier A, Kleijer WJ, et al: Molecular analysis of mutations in DNA polymerase eta in xeroderma pigmentosum-variant patients. Proc Natl Acad Sci USA. 99:815–820. 2002. View Article : Google Scholar : PubMed/NCBI
9	Faili A, Stary A, Delbos F, et al: A backup role of DNA polymerase kappa in Ig gene hypermutation only takes place in the complete absence of DNA polymerase eta. J Immunol. 182:6353–6359. 2009. View Article : Google Scholar : PubMed/NCBI
10	Kannouche P, Broughton BC, Volker M, Hanaoka F, Mullenders LH and Lehmann AR: Domain structure, localization and function of DNA polymerase eta, defective in xeroderma pigmentosum variant cells. Genes Dev. 15:158–172. 2001. View Article : Google Scholar : PubMed/NCBI
11	Yuasa M, Masutani C, Eki T and Hanaoka F: Genomic structure, chromosomal localization and identification of mutations in the xeroderma pigmentosum variant (XPV) gene. Oncogene. 19:4721–4728. 2000. View Article : Google Scholar : PubMed/NCBI
12	Tanioka M, Masaki T, Ono R, et al: Molecular analysis of DNA polymerase eta gene in Japanese patients diagnosed as xeroderma pigmentosum variant type. J Invest Dermatol. 127:1745–1751. 2007.PubMed/NCBI
13	Hentosh P, Benjamin T, Hall L, et al: Xeroderma pigmentosum variant: complementary molecular approaches to detect a 13 base pair deletion in the DNA polymerase eta gene. Exp Mol Pathol. 91:528–533. 2011. View Article : Google Scholar : PubMed/NCBI
14	Johnson RE, Prakash S and Prakash L: Efficient bypass of a thymine-thymine dimer by yeast DNA polymerase, Poleta. Science. 283:1001–1004. 1999. View Article : Google Scholar : PubMed/NCBI
15	Ohmori H, Friedberg EC, Fuchs RP, et al: The Y-family of DNA polymerases. Mol Cell. 8:7–8. 2001. View Article : Google Scholar
16	Daya-Grosjean L and Sarasin A: The role of UV induced lesions in skin carcinogenesis: an overview of oncogene and tumor suppressor gene modifications in xeroderma pigmentosum skin tumors. Mutat Res. 571:43–56. 2005. View Article : Google Scholar : PubMed/NCBI
17	Silverstein TD, Johnson RE, Jain R, et al: Structural basis for the suppression of skin cancers by DNA polymerase eta. Nature. 465:1039–1043. 2010. View Article : Google Scholar : PubMed/NCBI
18	Ziv O, Geacintov N, Nakajima S, Yasui A and Livneh Z: DNA polymerase zeta cooperates with polymerases kappa and iota in translesion DNA synthesis across pyrimidine photodimers in cells from XPV patients. Proc Natl Acad Sci USA. 106:11552–11557. 2009. View Article : Google Scholar : PubMed/NCBI
19	Masuda K, Ouchida R, Hikida M, et al: 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. 2007. View Article : Google Scholar : PubMed/NCBI
20	Song Y, Wang C, Peng B, et al: Phenotypes and genotypes in 2 DGI families with different DSPP mutations. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 102:360–374. 2006. View Article : Google Scholar : PubMed/NCBI
21	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods. 25:402–408. 2001.
22	Johnson RE, Washington MT, Prakash S and Prakash L: Fidelity of human DNA polymerase eta. J Biol Chem. 275:7447–7450. 2000. View Article : Google Scholar : PubMed/NCBI
23	Cruet-Hennequart S, Gallagher K, Sokol AM, Villalan S, Prendergast AM and Carty MP: DNA polymerase eta, a key protein in translesion synthesis in human cells. Subcell Biochem. 50:189–209. 2010. View Article : Google Scholar : PubMed/NCBI
24	Svoboda DL, Briley LP and Vos JM: Defective bypass replication of a leading strand cyclobutane thymine dimer in xeroderma pigmentosum variant cell extracts. Cancer Res. 58:2445–2448. 1998.
25	Masutani C, Araki M, Yamada A, et al: Xeroderma pigmentosum variant (XP-V) correcting protein from HeLa cells has a thymine dimer bypass DNA polymerase activity. EMBO J. 18:3491–3501. 1999. View Article : Google Scholar
26	Bradford PT, Goldstein AM, Tamura D, et al: Cancer and neurologic degeneration in xeroderma pigmentosum: long term follow-up characterises the role of DNA repair. J Med Genet. 48:168–176. 2011. View Article : Google Scholar : PubMed/NCBI
27	Gueranger Q, Stary A, Aoufouchi S, et al: 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. 2008. View Article : Google Scholar : PubMed/NCBI
28	Wang Y, Woodgate R, McManus TP, et al: 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. 2007. View Article : Google Scholar : PubMed/NCBI
29	Lemée F, Bergoglio V, Fernandez-Vidal A, et al: DNA polymerase theta up-regulation is associated with poor survival in breast cancer, perturbs DNA replication and promotes genetic instability. Proc Natl Acad Sci USA. 107:13390–13395. 2010.PubMed/NCBI