Set2 histone methyltransferase regulates transcription coupled-nucleotide excision repair in yeast

Selvam, Kathiresan; Plummer, Dalton A; Mao, Peng; Wyrick, John J.

doi:10.1371/journal.pgen.1010085

Cited by 9 publications

(12 citation statements)

References 81 publications

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“…Analysis of the resulting CPD‐seq reads showed clear enrichment of reads associated with lesions at dipyrimidines (i.e., TT, TC, CT, CC) in the UV‐irradiated DNA, but not in the No UV control (Figure 1a, b). Dipyrimidine enrichment was similar between the UVB and UVC‐treated samples, and both samples showed similar sequence preferences for CPD formation (i.e., TT > TC > CT > CC; see Figure 1a, b), as expected from previous studies (Mao et al, 2016, 2020; Mao & Wyrick, 2020; Selvam et al, 2022).…”

Section: Resultssupporting

confidence: 85%

Genome‐wide impact of cytosine methylation and DNA sequence context on UV‐induced CPD formation

Wilson

Wyrick

2023

Environ and Mol Mutagen

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Exposure to ultraviolet (UV) light is the primary etiological agent for skin cancers because UV damages cellular DNA. The most frequent form of UV damage is the cyclobutane pyrimidine dimer (CPD), which consists of covalent linkages between neighboring pyrimidine bases in DNA. In human cells, the 5’ position of cytosine bases in CG dinucleotides is frequently methylated, and methylated cytosines in the TP53 tumor suppressor are often sites of mutation hotspots in skin cancers. It has been argued that this is because cytosine methylation promotes UV‐induced CPD formation; however, the effects of cytosine methylation on CPD formation are controversial, with conflicting results from previous studies. Here, we use a genome‐wide method known as CPD‐seq to map UVB‐ and UVC‐induced CPDs across the yeast genome in the presence or absence in vitro methylation by the CpG methyltransferase M.SssI. Our data indicate that cytosine methylation increases UVB‐induced CPD formation nearly 2‐fold relative to unmethylated DNA, but the magnitude of induction depends on the flanking sequence context. Sequence contexts with a 5’ guanine base (e.g., GCCG and GTCG) show the strongest induction due to cytosine methylation, potentially because these sequence contexts are less efficient at forming CPD lesions in the absence of methylation. We show that cytosine methylation also modulates UVC‐induced CPD formation, albeit to a lesser extent than UVB. These findings can potentially reconcile previous studies, and define the impact of cytosine methylation on UV damage across a eukaryotic genome.This article is protected by copyright. All rights reserved.

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Section: Resultssupporting

confidence: 85%

Genome‐wide impact of cytosine methylation and DNA sequence context on UV‐induced CPD formation

Wilson

Wyrick

2023

Environ and Mol Mutagen

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“…This regulation by Set2 occurs at least partially because H3K36me antagonizes H3K36 acetylation (H3K36ac) by Gcn5, which promotes chromatin accessibility leading to increased end resection which in turn favors DSB repair by HR [ 148 ]. Set2 has also recently been reported to facilitate transcription coupled-nucleotide excision repair through H3K36 methylation in budding yeast [ 167 ] indicating that Set2 regulates multiple DNA repair pathways.…”

Section: Function Of Set2/setd2 and H3k36 Methylationmentioning

confidence: 99%

SETD2: from chromatin modifier to multipronged regulator of the genome and beyond

Molenaar

Leeuwen

2022

Cell. Mol. Life Sci.

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Histone modifying enzymes play critical roles in many key cellular processes and are appealing proteins for targeting by small molecules in disease. However, while the functions of histone modifying enzymes are often linked to epigenetic regulation of the genome, an emerging theme is that these enzymes often also act by non-catalytic and/or non-epigenetic mechanisms. SETD2 (Set2 in yeast) is best known for associating with the transcription machinery and methylating histone H3 on lysine 36 (H3K36) during transcription. This well-characterized molecular function of SETD2 plays a role in fine-tuning transcription, maintaining chromatin integrity, and mRNA processing. Here we give an overview of the various molecular functions and mechanisms of regulation of H3K36 methylation by Set2/SETD2. These fundamental insights are important to understand SETD2’s role in disease, most notably in cancer in which SETD2 is frequently inactivated. SETD2 also methylates non-histone substrates such as α-tubulin which may promote genome stability and contribute to the tumor-suppressor function of SETD2. Thus, to understand its role in disease, it is important to understand and dissect the multiple roles of SETD2 within the cell. In this review we discuss how histone methylation by Set2/SETD2 has led the way in connecting histone modifications in active regions of the genome to chromatin functions and how SETD2 is leading the way to showing that we also have to look beyond histones to truly understand the physiological role of an ‘epigenetic’ writer enzyme in normal cells and in disease.

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“…budding yeast (Guintini et al, 2022;Martinez et al, 2022). Furthermore, a yeast mutant deficient in global NER but proficient for TC-NER shows increased UV resistance when spurious transcription initiation is licensed, demonstrating the capacity of pervasive transcription to improve genome stability (Selvam et al, 2022).…”

Section: Take-awaymentioning

confidence: 99%

“…Conversely, it has been speculated that one reason why eukaryotes including yeast undergo genome‐wide pervasive transcription is to allow RNA polymerase to survey the genome for replisome blocking lesions for repair by TC‐NER before DNA replication (Ljungman, 2022), and direct evidence exists for this in bacteria as well as for telomeres in budding yeast (Guintini et al, 2022; Martinez et al, 2022). Furthermore, a yeast mutant deficient in global NER but proficient for TC‐NER shows increased UV resistance when spurious transcription initiation is licensed, demonstrating the capacity of pervasive transcription to improve genome stability (Selvam et al, 2022).…”

Section: Transcription Provides Mutational Vulnerabilities and Opport...mentioning

confidence: 99%

Transcription as source of genetic heterogeneity in budding yeast

Piguet,

Houseley

2024

Yeast

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Transcription presents challenges to genome stability both directly, by altering genome topology and exposing single‐stranded DNA to chemical insults and nucleases, and indirectly by introducing obstacles to the DNA replication machinery. Such obstacles include the RNA polymerase holoenzyme itself, DNA‐bound regulatory factors, G‐quadruplexes and RNA‐DNA hybrid structures known as R‐loops. Here, we review the detrimental impacts of transcription on genome stability in budding yeast, as well as the mitigating effects of transcription‐coupled nucleotide excision repair and of systems that maintain DNA replication fork processivity and integrity. Interactions between DNA replication and transcription have particular potential to induce mutation and structural variation, but we conclude that such interactions must have only minor effects on DNA replication by the replisome with little if any direct mutagenic outcome. However, transcription can significantly impair the fidelity of replication fork rescue mechanisms, particularly Break Induced Replication, which is used to restart collapsed replication forks when other means fail. This leads to de novo mutations, structural variation and extrachromosomal circular DNA formation that contribute to genetic heterogeneity, but only under particular conditions and in particular genetic contexts, ensuring that the bulk of the genome remains extremely stable despite the seemingly frequent interactions between transcription and DNA replication.

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Set2 histone methyltransferase regulates transcription coupled-nucleotide excision repair in yeast

Cited by 9 publications

References 81 publications

Genome‐wide impact of cytosine methylation and DNA sequence context on UV‐induced CPD formation

Genome‐wide impact of cytosine methylation and DNA sequence context on UV‐induced CPD formation

SETD2: from chromatin modifier to multipronged regulator of the genome and beyond

Transcription as source of genetic heterogeneity in budding yeast

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