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DNA polymerase η (PolH) is the product of the Xeroderma Pigmentosum Variant (XPV) gene and a well-characterized Y-family DNA polymerase for trans-lesion synthesis (TLS). Cells derived from XPV patients, that are deficient in PolH, are unable to bypass UV photoproducts and DNA adducts in an error-free manner and thus acquire genetic mutations. Here, we found that PolH can be induced by DNA damage in a p53-dependent manner and knockdown of PolH confers cells resistance to apoptosis induced by DNA damage agents in multiple cell lines and cell types. We also showed that the resistance to DNA damage-induced apoptosis is p53-dependent. To explore the underlying mechanism, we examined p53 activation following DNA damage in various cell lines. We found that p53 activation is impaired in PolH knockdown cells. More importantly, reconstitution of PolH into PolH knockdown cells restores p53 activation. Finally, we provided evidence that knockdown of PolH impairs ATM autophosphorylation and consequently, phosphorylation of Chk2 and p53. Together, we found that PolH has a novel role in the DNA damage checkpoint and a p53 target can modulate the DNA damage response and subsequently regulate p53 activation.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]