Structural basis for error-free replication of oxidatively damaged DNA by yeast DNA polymerase η.
7,8-dihydro-8-oxoguanine (8-oxoG) adducts are formed frequently by the attack of oxygen-free radicals on DNA. They are among the most mutagenic lesions in cells because of their dual coding potential, where, in addition to normal base-pairing of 8-oxoG(anti) with dCTP, 8-oxoG in the syn conformation can base pair with dATP, causing G to T transversions. We provide here for the first time a structural basis for the error-free replication of 8-oxoG lesions by yeast DNA polymerase η (Polη). We show that the open active site cleft of Polη can accommodate an 8-oxoG lesion in the anti conformation with only minimal changes to the polymerase and the bound DNA: at both the insertion and post-insertion steps of lesion bypass. Importantly, the active site geometry remains the same as in the undamaged complex and provides a basis for the ability of Polη to prevent the mutagenic replication of 8-oxoG lesions in cells.
Department of Structural & Chemical Biology, Mount Sinai School of Medicine, Box 1677, 1425 Madison Avenue, New York, NY 10029, USA.
Timothy D
TD
Silverstein
Rinku
R
Jain
Robert E
RE
Johnson
Louise
L
Prakash
Satya
S
Prakash
Aneel K
AK
Aggarwal
D020134:Catalytic Domain / Q000235:genetics; D003461:Crystallography; D018736:DNA Adducts / Q000737:chemistry / Q000235:genetics; D004260:DNA Repair; D004261:DNA Replication / Q000502:physiology*; D004259:DNA-Directed DNA Polymerase / Q000737:chemistry* / Q000378:metabolism*; D006147:Guanine / Q000031:analogs & derivatives / Q000737:chemistry; D008958:Models, Molecular; D011487:Protein Conformation; D012441:Saccharomyces cerevisiae / Q000201:enzymology*; D000099270:Y-Family DNA Polymerases
D018736:DNA Adducts; D004259:DNA-Directed DNA Polymerase; D006147:Guanine; C453560:7,8-dihydro-8-oxoguanine; C112338:Rad30 protein; D000099270:Y-Family DNA Polymerases