Mechanism of error-free and semitargeted mutagenic bypass of an aromatic amine lesion by Y-family polymerase Dpo4 Journal Article

   

Authors:	Rechkoblit, O.; Kolbanovskiy, A.; Malinina, L.; Geacintov, N. E.; Broyde, S.; Patel, D. J.
Article Title:	Mechanism of error-free and semitargeted mutagenic bypass of an aromatic amine lesion by Y-family polymerase Dpo4
Abstract:	The aromatic amine carcinogen 2-aminofluorene (AF) forms covalent adducts with DNA, predominantly with guanine at the C8 position. Such lesions are bypassed by Y-family polymerases such as Dpo4 via error-free and error-prone mechanisms. We show that Dpo4 catalyzes elongation from a correct 3′-terminal cytosine opposite [AF]G in a nonrepetitive template sequence with low efficiency. This extension leads to cognate full-length product, as well as mis-elongated products containing base mutations and deletions. Crystal structures of the Dpo4 ternary complex, with the 3′-terminal primer cytosine base opposite [AF]G in the anti conformation and with the AF moiety positioned in the major groove, reveal both accurate and misalignment-mediated mutagenic extension pathways. The mutagenic template-primer-dNTP arrangement is promoted by interactions between the polymerase and the bulky lesion rather than by a base pair-stabilized misaligment. Further extension leads to semitargeted mutations via this proposed polymerase-guided mechanism. © 2010 Nature America, Inc. All rights reserved.
Keywords:	unclassified drug; gene mutation; gene deletion; accuracy; protein; bacterial proteins; kinetics; crystal structure; models, molecular; crystallography, x-ray; catalysis; protein structure, secondary; fluorenes; dpo4 protein; dna polymerase beta; x-ray diffraction; aromatic amine; cytosine; parathion; ternary complex factor
Journal Title:	Nature Structural and Molecular Biology
Volume:	17
Issue:	3
ISSN:	1545-9993
Publisher:	Nature Publishing Group
Date Published:	2010-03-01
Start Page:	379
End Page:	388
Language:	English
DOI:	10.1038/nsmb.1771
PUBMED:	20154704
PROVIDER:	scopus
PMCID:	PMC4215948
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-77949270833&partnerID=40&md5=2b616ad313577070633908fe94a822a5
Notes:	--- - "Cited By (since 1996): 4" - "Export Date: 20 April 2011" - "CODEN: NSMBC" - "Source: Scopus"

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