DNA polymerase ζ cooperates with polymerases κ and ι in translesion DNA synthesis across pyrimidine photodimers in cells from XPV patients

Omer Ziv, Nicholas Geacintov, Satoshi Nakajima, Akira Yasui, Zvi Livneh

Research output: Contribution to journalArticle

Abstract

Human cells tolerate UV-induced cyclobutane pyrimidine dimers (CPD) by translesion DNA synthesis (TLS), carried out by DNA polymerase η, the POLH gene product. A deficiency in DNA polymerase η 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 ζ cooperates with DNA polymerases κ and ι to carry out error-prone TLS across a TT CPD. Moreover, DNA polymerases ζ and κ, but not ι, 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.

Original languageEnglish (US)
Pages (from-to)11552-11557
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number28
DOIs
StatePublished - Jul 14 2009

Keywords

  • Carcinogenesis
  • DNA repair
  • Lesion bypass
  • Replication
  • Ultraviolet

ASJC Scopus subject areas

  • General

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