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Mol Cancer Res. 2014 Aug;12(8):1128-39. doi: 10.1158/1541-7786.MCR-13-0502. Epub 2014 Apr 25.

Base excision repair defects invoke hypersensitivity to PARP inhibition.

Author information

  • 1Laboratory of Structural Biology, NIEHS, NIH, Research Triangle Park, North Carolina.
  • 2Laboratory of Structural Biology, NIEHS, NIH, Research Triangle Park, North Carolina wilson5@niehs.nih.gov.

Abstract

PARP-1 is important for the recognition of both endogenous and exogenous DNA damage, and binds to DNA strand breaks including intermediates of base excision repair (BER). Once DNA-bound, PARP-1 becomes catalytically activated synthesizing PAR polymers onto itself and other repair factors (PARylation). As a result, BER repair proteins such as XRCC1 and DNA polymerase β (pol β) are more efficiently and rapidly recruited to sites of DNA damage. In the presence of an inhibitor of PARP activity (PARPi), PARP-1 binds to sites of DNA damage, but PARylation is prevented. BER enzyme recruitment is hindered, but binding of PARP-1 to DNA is stabilized, impeding DNA repair and leading to double-strand DNA breaks (DSB). Deficiencies in pol β(-/-) and Xrcc1(-/-) cells resulted in hypersensitivity to the PARP inhibitor 4-AN and reexpression of pol β or XRCC1, in these contexts, reversed the 4-AN hypersensitivity phenotype. BER deficiencies also showed evidence of replication defects that lead to DSB-induced apoptosis upon PARPi treatment. Finally, the clinically relevant PARP inhibitors olaparib and veliparib also exhibited hypersensitivity in both pol β(-/-) and Xrcc1(-/-) BER-deficient cells. These results reveal heightened sensitivity to PARPi as a function of BER deficiency.

IMPLICATIONS:

BER deficiency represents a new therapeutic opportunity to enhance PARPi efficacy.

©2014 American Association for Cancer Research.

PMID:
24770870
[PubMed - in process]
PMCID:
PMC4135006
[Available on 2015/8/1]
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