Increased replication-associated single-stranded DNA promotes formaldehyde-induced mutagenesis in Saccharomyces cerevisiae
Abstract
Formaldehyde (FA) is an environmentally abundant and endogenously produced aldehyde that has been shown to cause DNA damage, mutagenesis, and carcinogenesis. Several studies have demonstrated that FA induces guanine mutations resulting in a mutation signature like SBS40. In this work, we use Saccharomyces cerevisiae to demonstrate that replication defects generating single-stranded DNA (ssDNA) caused by the downregulation of the major replicative polymerases results in elevated FA mutagenesis. We found that loss of Mrc1 (CLASPIN) resulted in a high accumulation of ssDNA and FA mutagenesis, and that these phenotypes were not dependent on Mrc1's checkpoint activity. Loss of DNA–protein crosslink repair results in elevated FA sensitivity with no alteration to mutagenesis, likely due to the inability of the fork to bypass unprocessed protein adducts. Finally, we show that FA-induced mutagenesis is dependent on Pol ζ-mediated translesion synthesis, while deficiencies in the template switching pathway do not alter error-free bypass of FA adducts. Overall, our work points toward replication-associated ssDNA as a major substrate for FA-induced damage and elucidates the pathways that function to prevent FA mutagenesis at replication forks.
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BibTeX
@article{blouin2026increased,
title = {{Increased replication-associated single-stranded DNA promotes formaldehyde-induced mutagenesis in Saccharomyces cerevisiae}},
author = {Thomas Blouin and Charlotte McGuinness and Kierra Marshall and Caroline Bazzle and Natalie Saini},
journal = {Genetics},
year = {2026},
month = jul,
doi = {10.1093/genetics/iyag189},
url = {https://doi.org/10.1093/genetics/iyag189},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Increased replication-associated single-stranded DNA promotes formaldehyde-induced mutagenesis in Saccharomyces cerevisiae
AU - Thomas Blouin
AU - Charlotte McGuinness
AU - Kierra Marshall
AU - Caroline Bazzle
AU - Natalie Saini
PY - 2026
DA - 2026/07/21
JO - Genetics
DO - 10.1093/genetics/iyag189
UR - https://doi.org/10.1093/genetics/iyag189
AB - Formaldehyde (FA) is an environmentally abundant and endogenously produced aldehyde that has been shown to cause DNA damage, mutagenesis, and carcinogenesis. Several studies have demonstrated that FA induces guanine mutations resulting in a mutation signature like SBS40. In this work, we use Saccharomyces cerevisiae to demonstrate that replication defects generating single-stranded DNA (ssDNA) caused by the downregulation of the major replicative polymerases results in elevated FA mutagenesis. We found that loss of Mrc1 (CLASPIN) resulted in a high accumulation of ssDNA and FA mutagenesis, and that these phenotypes were not dependent on Mrc1's checkpoint activity. Loss of DNA–protein crosslink repair results in elevated FA sensitivity with no alteration to mutagenesis, likely due to the inability of the fork to bypass unprocessed protein adducts. Finally, we show that FA-induced mutagenesis is dependent on Pol ζ-mediated translesion synthesis, while deficiencies in the template switching pathway do not alter error-free bypass of FA adducts. Overall, our work points toward replication-associated ssDNA as a major substrate for FA-induced damage and elucidates the pathways that function to prevent FA mutagenesis at replication forks.
SN - 0016-6731
SN - 1943-2631
ER -