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Significance In mammalian cells DNA polymerase ζ (polζ) appears critical for bypass of DNA damage and was expected to be important for UV-induced skin carcinogenesis. To investigate the response to UV radiation, we engineered mice lacking polζ in the epidermis, circumventing a requirement for embryonic development. These mice were much more sensitive to UVB radiation than predicted, failed to mount skin-regenerative responses, and did not develop UV-induced skin tumors. Even unirradiated polζ-deficient keratinocytes had a marked proliferation defect and increased chromosomal breaks. Thus in rapidly proliferating cells, polζ maintains levels of DNA breaks below a lethal threshold.

Dual role for mammalian DNA polymerase ζ in maintaining genome stability and proliferative responses