Base excision repair and design of small molecule inhibitors of human DNA polymerase β.
Base excision repair (BER) can protect a cell after endogenous or exogenous genotoxic stress, and a deficiency in BER can render a cell hypersensitive to stress-induced apoptotic and necrotic cell death, mutagenesis, and chromosomal rearrangements. However, understanding of the mammalian BER system is not yet complete as it is extraordinarily complex and has many back-up processes that complement a deficiency in any one step. Due of this lack of information, we are unable to make accurate predictions on therapeutic approaches targeting BER. A deeper understanding of BER will eventually allow us to conduct more meaningful clinical interventions. In this review, we will cover historical and recent information on mammalian BER and DNA polymerase β and discuss approaches toward development and use of small molecule inhibitors to manipulate BER. With apologies to others, we will emphasize results obtained in our laboratory and those of our collaborators.
Wilson
Samuel H
SH
Laboratory of Structural Biology, National Institute of Environmental Health Sciences, NIH, 111 T.W. Alexander Drive, Research Triangle Park, NC 27709, USA. wilson5@niehs.nih.gov
Beard
William A
WA
Shock
David D
DD
Batra
Vinod K
VK
Cavanaugh
Nisha A
NA
Prasad
Rajendra
R
Hou
Esther W
EW
Liu
Yuan
Y
Asagoshi
Kenjiro
K
Horton
Julie K
JK
Stefanick
Donna F
DF
Kedar
Padmini S
PS
Carrozza
Michael J
MJ
Masaoka
Aya
A
Heacock
Michelle L
ML
D000818:Animals; D019951:DNA Polymerase beta / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D004260:DNA Repair / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D057166:High-Throughput Screening Assays; D006801:Humans; D008958:Models, Molecular
D004791:Enzyme Inhibitors; D019951:DNA Polymerase beta