DNA polymerase β-dependent cell survival independent of XRCC1 expression

Base excision repair (BER) is a primary mechanism for repair of base lesions in DNA such as those formed by exposure to the DNA methylating agent methyl methanesulfonate (MMS). Both DNA polymerase 13 (pol beta)- and XRCC1 -deficient mouse fibroblasts are hypersensitive to MMS. This is linked to a repair deficiency as measured by accumulation of strand breaks and poly(ADP-ribose) (PAR). The interaction between pol 13 and XRCC1 is important for recruitment of pol beta to sites of DNA damage. Endogenous DNA damage can substitute for MMS-induced damage such that BER deficiency as a result of either pol beta- or XRCC1 -deletion is associated with sensitivity to PARP inhibitors. Pol beta shRNA was used to knock down pol beta in Xrcc1(+/+) and Xrcc1(-/-) mouse fibroblasts. We determined whether pol beta-mediated cellular resistance to MMS and PARP inhibitors resulted entirely from coordination with XRCC1 within the same BER sub-pathway. We find evidence for pol beta-dependent cell survival independent of XRCC1 expression for both types of agents. The results suggest a role for pol beta-dependent, XRCC1-independent repair. PAR immunofluorescence data are consistent with the hypothesis of a decrease in repair in both pol beta knock down cell variants. Published by Elsevier B.V.