DNA polymerase zeta cooperates with polymerases kappa and iota in translesion DNA synthesis across pyrimidine photodimers in cells from XPV patients.

Abstract

Human cells tolerate UV-induced cyclobutane pyrimidine dimers (CPD) by translesion DNA synthesis (TLS), carried out by DNA polymerase eta, the POLH gene product. A deficiency in DNA polymerase eta due to germ-line mutations in POLH causes the hereditary disease xeroderma pigmentosum variant (XPV), which is characterized by sunlight sensitivity and extreme predisposition to sunlight-induced skin cancer. XPV cells are UV hypermutable due to the activity of mutagenic TLS across CPD, which explains the cancer predisposition of the patients. However, the identity of the backup polymerase that carries out this mutagenic TLS was unclear. Here, we show that DNA polymerase zeta cooperates with DNA polymerases kappa and iota to carry out error-prone TLS across a TT CPD. Moreover, DNA polymerases zeta and kappa, but not iota, protect XPV cells against UV cytotoxicity, independently of nucleotide excision repair. This presents an extreme example of benefit-risk balance in the activity of TLS polymerases, which provide protection against UV cytotoxicity at the cost of increased mutagenic load.

• Authors: Omer Ziv, Nicholas Geacintov, Satoshi Nakajima, Akira Yasui, Zvi Livneh
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 106 Issue 28 Pg. 11552-7 (Jul 14 2009) ISSN: 1091-6490 [Electronic] United States
• PMID: 19564618 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Pyrimidine Dimers
• DNA
• DNA polymerase zeta
• DNA-Directed DNA Polymerase

Topics

• Cells, Cultured
• DNA (biosynthesis)
• DNA Repair (genetics)
• DNA-Directed DNA Polymerase (metabolism)
• Humans
• Models, Genetic
• Pyrimidine Dimers (metabolism)
• Ultraviolet Rays
• Xeroderma Pigmentosum (enzymology, genetics)