Participation of mouse DNA polymerase iota in strand-biased mutagenic bypass of UV photoproducts and suppression of skin cancer.
DNA polymerase iota (pol iota) is a conserved Y family enzyme that is implicated in translesion DNA synthesis (TLS) but whose cellular functions remain uncertain. To test the hypothesis that pol iota performs TLS in cells, we compared UV-induced mutagenesis in primary fibroblasts derived from wild-type mice to mice lacking functional pol eta, pol iota, or both. A deficiency in mouse DNA polymerase eta (pol eta) enhanced UV-induced Hprt mutant frequencies. This enhanced UV-induced mutagenesis and UV-induced mutagenesis in wild-type cells were strongly diminished in cells deficient in pol iota, indicating that pol iota participates in the bypass of UV photoproducts in cells. Moreover, a clear strand bias among UV-induced base substitutions was observed in wild-type cells that was diminished in pol eta- and pol iota-deficient mouse cells and abolished in cells deficient in both enzymes. These data suggest that these enzymes bypass UV photoproducts in an asymmetric manner. To determine whether pol iota status affects cancer susceptibility, we compared the UV-induced skin cancer susceptibility of wild-type mice to mice lacking functional pol eta, pol iota, or both. Although pol iota deficiency alone had no effect, UV-induced skin tumors in pol eta-deficient mice developed 4 weeks earlier in mice concomitantly deficient in pol iota. Collectively, these data reveal functions for pol iota in bypassing UV photoproducts and in delaying the onset of UV-induced skin cancer.
Dumstorf
Chad A
CA
Department of Pharmacology and Toxicology and James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202-1786, USA.
Clark
Alan B
AB
Lin
Qingcong
Q
Kissling
Grace E
GE
Yuan
Tao
T
Kucherlapati
Raju
R
McGregor
W Glenn
WG
Kunkel
Thomas A
TA
D000818:Animals; D002470:Cell Survival / Q000528:radiation effects; D002478:Cells, Cultured; D004249:DNA Damage; D004259:DNA-Directed DNA Polymerase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts; D051379:Mice; D018345:Mice, Knockout; D016296:Mutagenesis / Q000235:genetics*; D012680:Sensitivity and Specificity; D012878:Skin Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D014466:Ultraviolet Rays; D000094769:DNA Polymerase iota; D000099270:Y-Family DNA Polymerases
D004259:DNA-Directed DNA Polymerase; D000094769:DNA Polymerase iota; C112338:Rad30 protein; D000099270:Y-Family DNA Polymerases