The lyase activity of the DNA repair protein beta-polymerase protects from DNA-damage-induced cytotoxicity.
Small DNA lesions such as oxidized or alkylated bases are repaired by the base excision repair (BER) pathway. BER includes removal of the damaged base by a lesion-specific DNA glycosylase, strand scission by apurinic/apyrimidinic endonuclease, DNA resynthesis and ligation. BER may be further subdivided into DNA beta-polymerase (beta-pol)-dependent single-nucleotide repair and beta-pol-dependent or -independent long patch repair subpathways. Two important enzymatic steps in mammalian single-nucleotide BER are contributed by beta-pol: DNA resynthesis of the repair patch and lyase removal of 5'-deoxyribose phosphate (dRP). Fibroblasts from beta-pol null mice are hypersensitive to mono-functional DNA-methylating agents, resulting in increases in chromosomal damage, apoptosis and necrotic cell death. Here we show that only the dRP lyase activity of beta-pol is required to reverse methylating agent hypersensitivity in beta-pol null cells. These results indicate that removal of the dRP group is a pivotal step in BER in vivo. Persistence of the dRP moiety in DNA results in the hypersensitivity phenotype of beta-pol null cells and may signal downstream events such as apoptosis and necrotic cell death.
Sobol
R W
RW
Laboratory of Structural Biology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709-2233, USA.
Prasad
R
R
Evenski
A
A
Baker
A
A
Yang
X P
XP
Horton
J K
JK
Wilson
S H
SH
D002460:Cell Line; D002461:Cell Line, Transformed; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects* / Q000378:metabolism; D004249:DNA Damage; D019175:DNA Methylation; D019951:DNA Polymerase beta / Q000378:metabolism*; D004260:DNA Repair; D003855:Deoxyribose / Q000378:metabolism; D008190:Lyases / Q000378:metabolism*; D008741:Methyl Methanesulfonate / Q000633:toxicity*; D009153:Mutagens / Q000633:toxicity*; D014162:Transfection
D009153:Mutagens; D003855:Deoxyribose; D004247:DNA; D008741:Methyl Methanesulfonate; D019951:DNA Polymerase beta; D008190:Lyases