Futile short-patch DNA base excision repair of adenine:8-oxoguanine mispair.
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-oxoguanine 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 3'-dC 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.
Hashimoto
Keiji
K
Laboratory of Chemical Biology, Department of Pharmacological Sciences, State University of New York, Stony Brook, NY 11794-8651, USA.
Tominaga
Yohei
Y
Nakabeppu
Yusaku
Y
Moriya
Masaaki
M
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000225:Adenine / Q000378:metabolism*; D020137:Base Pair Mismatch; D045647:DNA Glycosylases / Q000378:metabolism; D011088:DNA Ligases / Q000378:metabolism; D004260:DNA Repair; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000378:metabolism; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D003838:Deoxyadenine Nucleotides / Q000378:metabolism; D003839:Deoxyadenosines / Q000737:chemistry / Q000378:metabolism; D003841:Deoxycytidine / Q000378:metabolism; D003843:Deoxycytidine Monophosphate / Q000378:metabolism; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism*; D005090:Exodeoxyribonucleases / Q000378:metabolism; D006801:Humans
D003838:Deoxyadenine Nucleotides; D003839:Deoxyadenosines; D003841:Deoxycytidine; D003843:Deoxycytidine Monophosphate; C012873:2'-deoxy-5'-adenosine monophosphate; D000080242:8-Hydroxy-2'-Deoxyguanosine; D004259:DNA-Directed DNA Polymerase; D005090:Exodeoxyribonucleases; D045647:DNA Glycosylases; C061738:mutY adenine glycosylase; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D011088:DNA Ligases; D003849:Deoxyguanosine; D000225:Adenine