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Flipping of alkylated DNA damage bridges base and nucleotide excision repair.
- Source :
-
Nature [Nature] 2009 Jun 11; Vol. 459 (7248), pp. 808-13. - Publication Year :
- 2009
-
Abstract
- Alkyltransferase-like proteins (ATLs) share functional motifs with the cancer chemotherapy target O(6)-alkylguanine-DNA alkyltransferase (AGT) and paradoxically protect cells from the biological effects of DNA alkylation damage, despite lacking the reactive cysteine and alkyltransferase activity of AGT. Here we determine Schizosaccharomyces pombe ATL structures without and with damaged DNA containing the endogenous lesion O(6)-methylguanine or cigarette-smoke-derived O(6)-4-(3-pyridyl)-4-oxobutylguanine. These results reveal non-enzymatic DNA nucleotide flipping plus increased DNA distortion and binding pocket size compared to AGT. Our analysis of lesion-binding site conservation identifies new ATLs in sea anemone and ancestral archaea, indicating that ATL interactions are ancestral to present-day repair pathways in all domains of life. Genetic connections to mammalian XPG (also known as ERCC5) and ERCC1 in S. pombe homologues Rad13 and Swi10 and biochemical interactions with Escherichia coli UvrA and UvrC combined with structural results reveal that ATLs sculpt alkylated DNA to create a genetic and structural intersection of base damage processing with nucleotide excision repair.
- Subjects :
- Alkylation
Binding Sites
Crystallography, X-Ray
DNA chemistry
DNA metabolism
Guanine analogs & derivatives
Guanine chemistry
Guanine metabolism
Humans
Models, Molecular
Protein Binding
Protein Conformation
Alkyl and Aryl Transferases chemistry
Alkyl and Aryl Transferases metabolism
DNA Damage
DNA Repair
Subjects
Details
- Language :
- English
- ISSN :
- 1476-4687
- Volume :
- 459
- Issue :
- 7248
- Database :
- MEDLINE
- Journal :
- Nature
- Publication Type :
- Academic Journal
- Accession number :
- 19516334
- Full Text :
- https://doi.org/10.1038/nature08076