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

Journal Article · Tue Mar 30 04:00:00 EDT 2010 · Nat. Struct. Mol. Biol.

DOI:https://doi.org/10.1038/nsmb.1771· OSTI ID:1002313

Rechkoblit, Olga; Kolbanovskiy, Alexander; Malinina, Lucy; Geacintov, Nicholas E; Broyde, Suse; Patel, Dinshaw J ^[1]

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1. NY Univ.

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{prime}-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{prime}-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.

• Research Organization: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
• Sponsoring Organization: USDOE
• OSTI ID: 1002313
• Journal Information: Nat. Struct. Mol. Biol., Journal Name: Nat. Struct. Mol. Biol. Journal Issue: (3) ; 03, 2010 Vol. 17; ISSN 1545-9985; ISSN 1545-9993
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

36 MATERIALS SCIENCE
ADDUCTS
AMINES
AROMATICS
CARCINOGENS
CRYSTAL STRUCTURE
CYTOSINE
DNA
EFFICIENCY
ELONGATION
GUANINE
MUTATIONS
POLYMERASES