Structure
Volume 19, Issue 6, 8 June 2011, Pages 821-832
Journal home page for Structure

Article
Implications for Damage Recognition during Dpo4-Mediated Mutagenic Bypass of m1G and m3C Lesions

https://doi.org/10.1016/j.str.2011.03.020Get rights and content
Under an Elsevier user license
open archive

Summary

DNA is susceptible to alkylation damage by a number of environmental agents that modify the Watson-Crick edge of the bases. Such lesions, if not repaired, may be bypassed by Y-family DNA polymerases. The bypass polymerase Dpo4 is strongly inhibited by 1-methylguanine (m1G) and 3-methylcytosine (m3C), with nucleotide incorporation opposite these lesions being predominantly mutagenic. Further, extension after insertion of both correct and incorrect bases, introduces additional base substitution and deletion errors. Crystal structures of the Dpo4 ternary extension complexes with correct and mismatched 3′-terminal primer bases opposite the lesions reveal that both m1G and m3C remain positioned within the DNA template/primer helix. However, both correct and incorrect pairing partners exhibit pronounced primer terminal nucleotide distortion, being primarily evicted from the DNA helix when opposite m1G or misaligned when pairing with m3C. Our studies provide insights into mechanisms related to hindered and mutagenic bypass of methylated lesions and models associated with damage recognition by repair demethylases.

Highlights

► Dpo4 is strongly inhibited and highly mutagenic during bypass of m1G and m3C lesions ► In the Dpo4 extension complexes, m1G and m3C remain positioned within the DNA helix ► The 3′-terminal A, G, T, and C primer bases opposite the lesions are mispositioned ► Mechanisms of methylation damage recognition by repair demethylases are discussed

Cited by (0)

4

Present address: Department of Structural and Chemical Biology, Mount Sinai School of Medicine, New York, NY 10029, USA