Impaired processing of DNA photoproducts and ultraviolet hypermutability with loss of p16INK4a or p19ARF.
Reduced DNA repair has been linked to an increased risk of cutaneous malignant melanoma, but insights into the molecular mechanisms of that link are scarce. The INK4a/ARF (CDKN2a) locus, which codes for the p16(INK4a) and p19ARF proteins, is often mutated in sporadic and familial malignant melanoma, but it has not been directly associated with reduced DNA repair. We transfected unirradiated mouse fibroblast cells with UV-treated DNA to measure DNA repair in normal, p16INK4a mutant, p19ARF mutant, or double mutant mouse host cells. Loss of either p16(INK4a) or p19ARF reduced the ability of the cells to process UV-induced DNA damage, independent of cell cycle effects incurred by the loss. These results may further explain why INK4a/ARF mutations predispose to malignant melanoma, a UV-induced tumor.
Sarkar-Agrawal
Papri
P
Department of Dermatology, Boston University School of Medicine, Boston, MA 02118, USA.
Vergilis
Irene
I
Sharpless
Norman E
NE
DePinho
Ronald A
RA
Rünger
Thomas M
TM
D000818:Animals; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000528:radiation effects; D004249:DNA Damage / Q000528:radiation effects; D004260:DNA Repair / Q000528:radiation effects; D005347:Fibroblasts / Q000378:metabolism / Q000528:radiation effects; D019942:Genes, p16 / Q000528:radiation effects*; D008545:Melanoma / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009154:Mutation; D012878:Skin Neoplasms / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics* / Q000528:radiation effects; D014466:Ultraviolet Rays
C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D025803:Tumor Suppressor Protein p14ARF