Completion of base excision repair by mammalian DNA ligases.
Three mammalian genes encoding DNA ligases--LIG1, LIG3, and LIG4--have been identified. Genetic, biochemical, and cell biology studies indicate that the products of each of these genes play a unique role in mammalian DNA metabolism. Interestingly, cell lines deficient in either DNA ligase I (46BR.1G1) or DNA ligase III (EM9) are sensitive to simple alkylating agents. One interpretation of these observations is that DNA ligases I and III participate in functionally distinct base excision repair (BER) subpathways. In support of this idea, extracts from both DNA ligase-deficient cell lines are defective in catalyzing BER in vitro and both DNA ligases interact with other BER proteins. DNA ligase I interacts directly with proliferating cell nuclear antigen (PCNA) and DNA polymerase beta (Pol beta), linking this enzyme with both short-patch and long-patch BER. In somatic cells, DNA ligase III alpha forms a stable complex with the DNA repair protein Xrcc1. Although Xrcc1 has no catalytic activity, it also interacts with Pol beta and poly(ADP-ribose) polymerase (PARP), linking DNA ligase III alpha with BER and single-strand break repair, respectively. Biochemical studies suggest that the majority of short-patch base excision repair events are completed by the DNA ligase III alpha/Xrcc1 complex. Although there is compelling evidence for the participation of PARP in the repair of DNA single-strand breaks, the role of PARP in BER has not been established.
Tomkinson
A E
AE
Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78245, USA.
Chen
L
L
Dong
Z
Z
Leppard
J B
JB
Levin
D S
DS
Mackey
Z B
ZB
Motycka
T A
TA
D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D003001:Cloning, Molecular; D006224:Cricetinae; D003412:Cricetulus; D004249:DNA Damage; D011088:DNA Ligases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004260:DNA Repair / Q000235:genetics / Q000502:physiology*; D018076:DNA, Complementary / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D005347:Fibroblasts; D005796:Genes; D005816:Genetic Complementation Test; D006801:Humans; D007527:Isoenzymes / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D046911:Macromolecular Substances; D008322:Mammals / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D000076105:X-ray Repair Cross Complementing Protein 1
D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D007527:Isoenzymes; D046911:Macromolecular Substances; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; D011088:DNA Ligases