TY - JOUR
T1 - Futile short-patch DNA base excision repair of adenine
T2 - 8-oxoguanine mispair
AU - Hashimoto, Keiji
AU - Tominaga, Yohei
AU - Nakabeppu, Yusaku
AU - Moriya, Masaaki
N1 - Funding Information:
We thank Luis Blanco, Carlos de los Santos, Paul Fisher, Fumio Hanaoka, Thomas Kunkel, Tomas Lindahl, Holly Miller, Haruo Ohmori, Larry Thompson, Alan Tomkinson and Roger Woodgate for enzymes and expression vectors. We also thank Cecilia Torres for oligonucleotide synthesis. This work was supported by NCI, National Institutes of Health, United States Public Health Service Grants (CA47995 and CA76163), the Ministry of Education, Culture, Sports, Science, and Technology of Japan (15025257), and the Japan Society for the Promotion of Science (15590347 and 16390119).
PY - 2004
Y1 - 2004
N2 - 8-Oxo-7, 8-dihydrodeoxyguanosine (8-oxo-dG), one of the representative oxidative DNA lesions, frequently mispairs with the incoming dAMP during mammalian DNA replication. Mispaired dA is removed by post-replicative base excision repair (BER) initiated by adenine DNA glycosylase, MYH, creating an apurinic (AP) site. The subsequent mechanism ensuring a dC:8-oxo-dG pair, a substrate for 8-oxo-guanine DNA glycosylase (OGG1), remains to be elucidated. At the nucleotide insertion step, none of the mammalian DNA polymerases examined exclusively inserted dC opposite 8-oxo-dG that was located in a gap. AP endonuclease 1, which possesses 3′→5′ exonuclease activity and potentially serves as a proofreader, did not discriminate dA from dC that was located opposite 8-oxo-dG. However, human DNA ligases I and III joined 3′-dA terminus much more efficiently than 3AC terminus when paired to 8-oxo-dG. In reconstituted short-patch BER, repair products contained only dA opposite 8-oxo-dG. These results indicate that human DNA ligases discriminate dC from dA and that MYH-initiated short-patch BER is futile and hence this BER must proceed to long-patch repair, even if it is initiated as short-patch repair, through strand displacement synthesis from the ligation-resistant dC terminus to generate the OGG1 substrate, dC:8-oxo-dG pair.
AB - 8-Oxo-7, 8-dihydrodeoxyguanosine (8-oxo-dG), one of the representative oxidative DNA lesions, frequently mispairs with the incoming dAMP during mammalian DNA replication. Mispaired dA is removed by post-replicative base excision repair (BER) initiated by adenine DNA glycosylase, MYH, creating an apurinic (AP) site. The subsequent mechanism ensuring a dC:8-oxo-dG pair, a substrate for 8-oxo-guanine DNA glycosylase (OGG1), remains to be elucidated. At the nucleotide insertion step, none of the mammalian DNA polymerases examined exclusively inserted dC opposite 8-oxo-dG that was located in a gap. AP endonuclease 1, which possesses 3′→5′ exonuclease activity and potentially serves as a proofreader, did not discriminate dA from dC that was located opposite 8-oxo-dG. However, human DNA ligases I and III joined 3′-dA terminus much more efficiently than 3AC terminus when paired to 8-oxo-dG. In reconstituted short-patch BER, repair products contained only dA opposite 8-oxo-dG. These results indicate that human DNA ligases discriminate dC from dA and that MYH-initiated short-patch BER is futile and hence this BER must proceed to long-patch repair, even if it is initiated as short-patch repair, through strand displacement synthesis from the ligation-resistant dC terminus to generate the OGG1 substrate, dC:8-oxo-dG pair.
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U2 - 10.1093/nar/gkh909
DO - 10.1093/nar/gkh909
M3 - Article
C2 - 15531653
AN - SCOPUS:10244255214
VL - 32
SP - 5928
EP - 5934
JO - Nucleic Acids Research
JF - Nucleic Acids Research
SN - 0305-1048
IS - 19
ER -