Structure-function analysis of human enzymes initiating nucleobase repair in DNA and RNA
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In humans, there are four known glycosylases that initiate repair of uracils in DNA. These are UNG, TDG, SMUG1, and MBD4. It was proposed that the replication independent SMUG1 was the main enzyme initiating removal of deaminated cytosine, whereas UNG2 was responsible for replication associated repair of mis-incorporated dUTP (Nilsen et al., 2001). We aimed at elucidating the specific function of the two main human uracil-DNA glycosylases in vitro and in vivo to further clarify their distinct roles in repair of uracils in the genome (Paper I). In Paper II, we continued the in-depth analysis of the distinct roles of hUNG2 and hSMUG1. We wanted to investigate whether hUNG2 and hSMUG1 coordinated the subsequent step in BER differentially, to characterize active-site residues in hSMUG1, and to elucidate the role of the extended DNA minor-groove intercalating motif of hSMUG1 in binding of the complementary DNA strand.
Has partsKavli, Bodil; Sundheim, Ottar; Akbari, Mansour; Otterlei, Marit; Nilsen, Hilde; Skorpen, Frank; Aas, Per Arne; Hagen, Lars; Krokan, Hans E; Slupphaug, Geir. hUNG2 Is the Major Repair Enzyme for Removal of Uracil from U:A Matches, U:G Mismatches, and U in Single-stranded DNA, with hSMUG1 as a Broad Specificity Backup. J. Biol. Chem. 227(42): 39926-39936, 2002.
Pettersen, Henrik Sahlin; Sundheim, Ottar; Giljam, Karin Margaretha. Uracil–DNA glycosylases SMUG1 and UNG2 coordinate the initial steps of base excision repair by distinct mechanisms. Nucleic Acids Research. 35(12): 3879-3879, 2007.
Aas, Per Arne; Otterlei, Marit; Falnes, Pål Ø; Vågbø, Cathrine B.; Skorpen, Frank; Akbari, Mansour; Sundheim, Ottar; Bjørås, Magnar; Slupphaug, Geir; Seeberg, Erling; Krokan, Hans E.. Human and bacterial oxidative demethylases repair alkylation damage in both RNA and DNA. Nature. 421, 2003.
Falnes, Pål Ø; Bjørås, Magnar; Aas, Per Arne; Sundheim, Ottar; Seeberg, Erling. Substrate specificities of bacterial and human AlkB proteins. Nucleic Acids Research. 32(11): 3456-3461, 2004.
Sundheim, Ottar; Vågbø, Cathrine B; Bjørås, Magnar; Sousa, Mirta M. L; Talstad, Vivi; Aas, Per Arne; Drabløs, Finn; Krokan, Hans E; Tainer, John A; Slupphaug, Geir. Human ABH3 structure and key residues for oxidative demethylation to reverse DNA/RNA damage. The EMBO Journal. 25: 3389-3397, 2006.