Structural highlights
Function
MUTY_GEOSE Base excision repair (BER) glycosylase that initiates repair of A:oxoG to C:G by removing the inappropriately paired adenine base from the DNA backbone, generating an abasic site product (PubMed:25995449) (PubMed:14961129). 8-oxoguanine (oxoG) is a genotoxic DNA lesion resulting from oxidation of guanine; this residue is misread by replicative DNA polymerases, that insert adenine instead of cytosine opposite the oxidized damaged base. Shows a powerful dicrimination of A versus C, since it does not cleave cytosine in oxoG:C pairs (PubMed:25995449). May also be able to remove adenine from A:G mispairs, although this activity may not be physiologically relevant (PubMed:14961129).[1] [2]
Publication Abstract from PubMed
The adenine glycosylase MutY selectively initiates repair of OG:A lesions and, by comparison, avoids G:A mispairs. The ability to distinguish these closely related substrates relies on the C-terminal domain of MutY which structurally resembles MutT. To understand the mechanism for substrate specificity, we crystallized MutY in complex with DNA containing G across from the high-affinity azaribose transition state analog. Our structure shows that G is accommodated by the OG site and highlights the role of a serine residue in OG versus G discrimination. The functional significance of Ser308 and its neighboring residues was evaluated by mutational analysis, revealing the critical importance of a beta-loop in the C-terminal domain for mutation suppression in cells, and biochemical performance in vitro. This loop comprising residues Phe307, Ser308, and His309 (Geobacillus stearothermophilus sequence positions) is conserved in MutY but absent in MutT and other DNA repair enzymes, and may therefore serve as a MutY-specific target exploitable by chemical biological probes.
Structural basis for finding OG lesions and avoiding undamaged G by the DNA glycosylase MutY.,Russelburg LP, O'Shea Murray VL, Demir M, Knutsen KR, Sehgal SL, Cao S, David SS, Horvath MP ACS Chem Biol. 2019 Dec 12. doi: 10.1021/acschembio.9b00639. PMID:31829624[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Wang L, Lee SJ, Verdine G. Structural Basis for Avoidance of Promutagenic DNA Repair by MutY Adenine DNA Glycosylase. J Biol Chem. 2015 May 20. pii: jbc.M115.657866. PMID:25995449 doi:http://dx.doi.org/10.1074/jbc.M115.657866
- ↑ Fromme JC, Banerjee A, Huang SJ, Verdine GL. Structural basis for removal of adenine mispaired with 8-oxoguanine by MutY adenine DNA glycosylase. Nature. 2004 Feb 12;427(6975):652-6. PMID:14961129 doi:10.1038/nature02306
- ↑ Russelburg LP, O'Shea Murray VL, Demir M, Knutsen KR, Sehgal SL, Cao S, David SS, Horvath MP. Structural basis for finding OG lesions and avoiding undamaged G by the DNA glycosylase MutY. ACS Chem Biol. 2019 Dec 12. doi: 10.1021/acschembio.9b00639. PMID:31829624 doi:http://dx.doi.org/10.1021/acschembio.9b00639
