Journal
SCIENTIFIC REPORTS
Volume 7, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41598-017-17643-0
Keywords
-
Categories
Funding
- core grant of the MRC London Institute of Medical Sciences (RCUK) [MC-A658-5TY10]
- Leverhulme Foundation [RPG-2016-214]
- start-up grant from Imperial College London
- U.S. Public Health Service Grant - Department of Health and Human Services [CA40605]
- MRC [MC_UP_1102/5] Funding Source: UKRI
- Medical Research Council [1375534, 1583062, MC_UP_1102/5] Funding Source: researchfish
Ask authors/readers for more resources
Translesion DNA synthesis is an essential process that helps resume DNA replication at forks stalled near bulky adducts on the DNA. Benzo[a]pyrene (B[a]P) is a polycyclic aromatic hydrocarbon (PAH) that can be metabolically activated to benzo[a] pyrene diol epoxide (BPDE), which then can react with DNA to form carcinogenic DNA adducts. Here, we have used single-molecule florescence resonance energy transfer (smFRET) experiments, classical molecular dynamics simulations, and nucleotide incorporation assays to investigate the mechanism by which the model Y-family polymerase, Dpo4, bypasses a (+)-cis-B[a]P-N-2-dG adduct in DNA. Our data show that when (+)-cis-B[a]P-N-2-dG is the templating base, the B[a]P moiety is in a non-solvent exposed conformation stacked within the DNA helix, where it effectively blocks nucleotide incorporation across the adduct by Dpo4. However, when the media contains a small amount of dimethyl sulfoxide (DMSO), the adduct is able to move to a solvent-exposed conformation, which enables error-prone DNA replication past the adduct. When the primer terminates across from the adduct position, the addition of DMSO leads to the formation of an insertion complex capable of accurate nucleotide incorporation.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available