TY - JOUR
T1 - Dual role for mammalian DNA polymerase ζ in maintaining genome stability and proliferative responses
AU - Lange, Sabine S.
AU - Bedford, Ella
AU - Reh, Shelley
AU - Wittschieben, John P.
AU - Carbajal, Steve
AU - Kusewitt, Donna F.
AU - DiGiovanni, John
AU - Wood, Richard D.
PY - 2013/2/19
Y1 - 2013/2/19
N2 - DNApolymerase ζ (polζ) is critical for bypass ofDNAdamage and the associated mutagenesis, but also has unique functions in mammals. It is required for embryonic development and for viability of hematopoietic cells, but, paradoxically, skin epithelia appear to survive polζ deletion. We wished to determine whether polζ functions in a tissue-specific manner and how polζ status influences skin tumorigenesis. Mice were produced in which Rev3L (the catalytic subunit of polζ) was deleted in tissues expressing keratin 5. Efficient epidermal deletion of Rev3L was tolerated but led to skin and hair abnormalities, accompanied by evidence of DNA breaks. Unchallenged mice developed tumors in keratin 5-expressing tissues with age, consistent with the chromosomal instability accompanying a polζ defect.Unexpectedly, mice with the Rev3L deletionweremuchmore sensitive to UVB radiation than mice defective in other DNA repair genes. Following irradiation, polζ-defective mice failed to mount skin-regenerative responses and responded to stress by mobilizing melanocytes to the epidermis. However, they did not develop skin tumors after chronic UVB irradiation. To determine the proliferative potential of polζ-deficient skin epithelia, keratinocytes were isolated and examined. These keratinocytes harbored chromosomal gaps and breaks and exhibited a striking proliferation defect. These results can be unified by a model in which slowly dividing cells accumulate replication-associated DNA breaks but otherwise survive Rev3L deletion, but functional polζ is essential for responses requiring rapid proliferation, both in cell culture and in vivo. The results reveal a biological role for mammalian polζ in tolerating DNA damage and enabling proliferative responses in vivo.
AB - DNApolymerase ζ (polζ) is critical for bypass ofDNAdamage and the associated mutagenesis, but also has unique functions in mammals. It is required for embryonic development and for viability of hematopoietic cells, but, paradoxically, skin epithelia appear to survive polζ deletion. We wished to determine whether polζ functions in a tissue-specific manner and how polζ status influences skin tumorigenesis. Mice were produced in which Rev3L (the catalytic subunit of polζ) was deleted in tissues expressing keratin 5. Efficient epidermal deletion of Rev3L was tolerated but led to skin and hair abnormalities, accompanied by evidence of DNA breaks. Unchallenged mice developed tumors in keratin 5-expressing tissues with age, consistent with the chromosomal instability accompanying a polζ defect.Unexpectedly, mice with the Rev3L deletionweremuchmore sensitive to UVB radiation than mice defective in other DNA repair genes. Following irradiation, polζ-defective mice failed to mount skin-regenerative responses and responded to stress by mobilizing melanocytes to the epidermis. However, they did not develop skin tumors after chronic UVB irradiation. To determine the proliferative potential of polζ-deficient skin epithelia, keratinocytes were isolated and examined. These keratinocytes harbored chromosomal gaps and breaks and exhibited a striking proliferation defect. These results can be unified by a model in which slowly dividing cells accumulate replication-associated DNA breaks but otherwise survive Rev3L deletion, but functional polζ is essential for responses requiring rapid proliferation, both in cell culture and in vivo. The results reveal a biological role for mammalian polζ in tolerating DNA damage and enabling proliferative responses in vivo.
KW - Carcinogenesis
KW - DNA replication
KW - Double-strand breaks
KW - UV radiation
UR - http://www.scopus.com/inward/record.url?scp=84874273451&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84874273451&partnerID=8YFLogxK
U2 - 10.1073/pnas.1217425110
DO - 10.1073/pnas.1217425110
M3 - Article
C2 - 23386725
AN - SCOPUS:84874273451
SN - 0027-8424
VL - 110
SP - E687-E696
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 8
ER -