Y-Family DNA polymerases help to maintain genome stability by translesion synthesis (TLS) across DNA damage, to rescue stalled replication forks. The larger and open active sites of these polymerases help them tolerate bulk and distortion introduced by DNA lesions. In humans, the Y-family DNA polymerase ? (pol ?) is essential for the bypass of cyclobutane pyrimidine dimers, and it is also involved in replication past 8-oxo-7, 8-dihydro-2'-deoxyguanosine (8-oxoG), one of the most abundant DNA lesions in genome, mainly caused by reduced oxygen species formed during aerobic cellular metabolism. Our results show that human pol ? favors error-free bypass of 8-oxoG and exhibits similar catalytic activities for insertion C opposite 8-oxoG and undamaged G. However, the misincorporation rate for 8-oxoG is 200 times of that for replication past G. The crystal structures of pol h-oligonucleotide-dNTP complexes show that Arg-61 directly interacts with the incoming dNTPs and plays a key role in insertion. Mutating this residue to Lys leads to elevated misincorporation compared with wild type pol ?. (Supported in part by USPHS grant R01 ES010375)

Mechanism of 8-Oxo-7, 8-dihydro-2'-deoxyguanosine bypass by human DNA polymerase ?

248th National Meeting (2014)

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