Formaldehyde-induced mutagenesis in Saccharomyces cerevisiae: molecular properties and the roles of repair and bypass systems.
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| Abstract |
Although DNA-protein cross-links (DPCs) pose a significant threat to genome stability, they remain a poorly understood class of DNA lesions. To define genetic impacts of DPCs on eukaryotic cells in molecular terms, we used a sensitive Saccharomyces cerevisiae frameshift-detection assay to analyze mutagenesis by formaldehyde (HCHO), and its response to nucleotide excision repair (NER) and translesion DNA synthesis (TLS). Brief exposure to HCHO was mutagenic for NER-defective rad14 strains but not for a corresponding RAD14 strain, nor for a rad14 strain lacking both Polζ and Polη TLS polymerases. This confirmed that HCHO-generated DNA lesions can trigger error-prone TLS and are substrates for the NER pathway. Sequencing revealed that HCHO-induced single-base-pair insertions occurred primarily at one hotspot; most of these insertions were also complex, changing an additional base-pair nearby. Most of the HCHO-induced mutations required both Polζ and Polη, providing a striking example of cooperativity between these two TLS polymerases during bypass of a DNA lesion formed in vivo. The similar molecular properties of HCHO-induced and spontaneous complex +1 insertions detected by this system suggest that DPCs which form in vivo during normal metabolism may contribute characteristic events to the spectra of spontaneous mutations in NER-deficient cells.
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| Authors | Dennis Grogan, Sue Jinks-Robertson |
| Journal | Mutation research (Mutat Res) Vol. 731 Issue 1-2 Pg. 92-8 (Mar 01 2012) ISSN: 0027-5107 [Print] Netherlands |
| PMID | 22197481 (Publication Type: Journal Article, Research Support, N.I.H., Extramural) |
| Copyright | Copyright © 2011 Elsevier B.V. All rights reserved. |
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