The accurate bypass of pyrimidine dimers by DNA polymerase eta contributes to ultraviolet-induced mutagenesis

Menck, C.F.M.; Galhardo, R.S.; Quinet, A.

doi:10.1016/j.mrfmmm.2023.111840

Cited by 4 publications

(3 citation statements)

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“…[ 67 , 68 , 69 ] Even error‐free bypass of a deaminated CPD by DNA polymerase eta would result in a C>T mutation, since it would correctly insert an adenine opposite the uracil base in the deaminated CPD. [ 49 , 53 ] Since human cells proliferate more slowly than yeast (i.e., >24 hours in human cells versus ∼1.5 hours in yeast), cytosine deamination in unrepaired CPDs may play a disproportionately more important role in UV mutagenesis, [ 5 , 70 , 71 ] potentially contributing to the enrichment of C>T substitutions in human skin cancers.…”

Section: Discussionmentioning

confidence: 99%

“…[34] In cells lacking POLH/XPV, these TT photoproducts are likely bypassed in an error-prone manner by an alternative TLS polymerase, such as DNA polymerase iota or kappa. [49][50][51][52][53][54][55] XPV −/− tumors also showed elevated T>A substitutions in an NTA sequence context (i.e., ATA>AAA, CTA>CAA, GTA>GAA, and TTA>TAA). Moreover, this mutation class was found to have the opposite transcriptional asymmetry of UV signature mutations (i.e., enrichment of T>A substitutions on the transcribed strand of genes).…”

Section: Species-specific Differences In Uv Mutation Spectra Are Caus...mentioning

confidence: 99%

“…[ 34 ] In cells lacking POLH/XPV, these TT photoproducts are likely bypassed in an error‐prone manner by an alternative TLS polymerase, such as DNA polymerase iota or kappa. [ 49 , 50 , 51 , 52 , 53 , 54 , 55 ]…”

Section: Species‐specific Differences In Uv Mutation Spectra Are Caus...mentioning

confidence: 99%

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The Surprising Diversity of UV‐Induced Mutations

Laughery,

Wilson,

Sewell

et al. 2024

Advanced Genetics

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Ultraviolet (UV) light is the most pervasive environmental mutagen and the primary cause of skin cancer. Genome sequencing of melanomas and other skin cancers has revealed that the vast majority of somatic mutations in these tumors are cytosine‐to‐thymine (C>T) substitutions in dipyrimidine sequences, which, together with tandem CC>TT substitutions, comprise the canonical UV mutation “signature”. These mutation classes are caused by DNA damage directly induced by UV absorption, namely cyclobutane pyrimidine dimers (CPDs) or 6‐4 pyrimidine‐pyrimidone photoproducts (6‐4PP), which form between neighboring pyrimidine bases. However, many of the key driver mutations in melanoma do not fit this mutation signature, but instead are caused by T>A, T>C, C>A, or AC>TT substitutions, frequently occurring in non‐dipyrimidine sequence contexts. This article describes recent studies indicating that UV light causes a more diverse spectrum of mutations than previously appreciated, including many of the mutation classes observed in melanoma driver mutations. Potential mechanisms for these diverse mutation signatures are discussed, including UV‐induced pyrimidine‐purine photoproducts and indirect DNA damage induced by UVA light. Finally, the article reviews recent findings indicating that human DNA polymerase eta normally suppresses these non‐canonical UV mutation classes, which can potentially explain why canonical C>T substitutions predominate in human skin cancers.

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Section: Discussionmentioning

confidence: 99%

Section: Species-specific Differences In Uv Mutation Spectra Are Caus...mentioning

confidence: 99%

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The Surprising Diversity of UV‐Induced Mutations

Laughery,

Wilson,

Sewell

et al. 2024

Advanced Genetics

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Spontaneous and environment induced genomic alterations in yeast model

Li,

Qi,

Zhu

et al. 2025

Cell Insight

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Patterns of spontaneous and induced genomic alterations in Yarrowia lipolytica

Xiong,

Fang,

et al. 2024

Appl Environ Microbiol

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This study explored the genomic alterations in Yarrowia lipolytica , a key yeast in industrial biotechnology, under both spontaneous and mutagen-induced conditions. Our findings reveal that spontaneous mutations occur at a rate of approximately 4 × 10 −10 events per base pair per cell division, primarily manifesting as single-nucleotide variations (SNVs) and small insertions and deletions (InDels). Notably, C-to-T/G-to-A transitions and C-to-A/G-to-T transversions dominate the spontaneous SNVs, while 1 bp deletions, likely resulting from template slippage, are the most frequent InDels. Furthermore, chromosomal aneuploidy and rearrangements occur, albeit at a lower frequency. Exposure to ultraviolet (UV) light, methylmethane sulfonate (MMS), and Zeocin significantly enhances the rates of SNVs and alters their mutational spectra in distinct patterns. Notably, Zeocin-induced SNVs are predominantly T-to-A and T-to-G substitutions, often occurring within the 5′-TGT * −3′ motif ( * denotes the mutated base). Additionally, Zeocin exhibits a higher potency in stimulating InDels compared to UV and MMS. Translesion DNA synthesis is implicated as the primary mechanism behind most Zeocin-induced SNVs and some InDels, whereas non-homologous end joining serves as the main pathway for Zeocin-mediated InDels. Intriguingly, the study identifies the gene YALI1_E21053g , encoding a protein kinase, as negatively associated with Zeocin resistance. Overall, our results not only deepened our knowledge about the genome evolution in Y. lipolytica but also provided reference to develop innovative strategies to harness its genetic potential. IMPORTANCE Yarrowia lipolytica exhibits high environmental stress tolerance and lipid metabolism capabilities, making it a microorganism with significant industrial application potential. In this study, we investigated the genomic variation and evolutionary patterns of this yeast under both spontaneous and induced mutation conditions. Our results reveal distinctive mutation spectra induced by different mutagenic conditions and elucidate the underlying genetic mechanisms. We further highlight the roles of non-homologous end joining and translesion synthesis pathways in Zeocin-induced mutations, demonstrating that such treatments can rapidly confer drug resistance to the cells. Overall, our research enhances the understanding of how yeast genomes evolve under various conditions and provides guidance for developing more effective mutagenesis and breeding techniques.

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The accurate bypass of pyrimidine dimers by DNA polymerase eta contributes to ultraviolet-induced mutagenesis

Cited by 4 publications

References 127 publications

The Surprising Diversity of UV‐Induced Mutations

The Surprising Diversity of UV‐Induced Mutations

Spontaneous and environment induced genomic alterations in yeast model

Patterns of spontaneous and induced genomic alterations in Yarrowia lipolytica

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