Abstract
Helix-distorting DNA lesions, including ultraviolet (UV) light-induced damage, are repaired by the global genomic-nucleotide excision repair (GG-NER) and transcription coupled-nucleotide excision repair (TC-NER) pathways. Previous studies have shown that histone post-translational modifications (PTMs) such as histone acetylation and methylation can promote GG-NER in chromatin. Whether histone PTMs also regulate the repair of DNA lesions by the TC-NER pathway in transcribed DNA is unknown. Here, we report that histone H3 K36 methylation (H3K36me) by the Set2 histone methyltransferase in yeast regulates TC-NER. Mutations in Set2 or H3K36 result in UV sensitivity that is epistatic with Rad26, the primary TC-NER factor in yeast, and cause a defect in the repair of UV damage across the yeast genome. We further show that mutations in Set2 or H3K36 in a GG-NER deficient strain (i.e., rad16Δ) partially rescue its UV sensitivity. Our data indicate that deletion of SET2 rescues UV sensitivity in a GG-NER deficient strain by activating cryptic antisense transcription, so that the non-transcribed strand (NTS) of yeast genes is repaired by TC-NER. These findings indicate that Set2 methylation of H3K36 establishes transcriptional asymmetry in repair by promoting canonical TC-NER of the transcribed strand (TS) and suppressing cryptic TC-NER of the NTS.
Highlights
The nucleotide excision repair (NER) pathway is critically important for removing bulky, helixdistorting DNA lesions, such as UV-induced cyclobutane pyrimidine dimers (CPDs) [1,2]
UV damage is repaired by the nucleotide excision repair pathway, which is triggered either by directly sensing UV damage or by sensing the stalling of an RNA polymerase enzyme at UV damage during transcription
Set2 is solely responsible for methylation of H3K36 [18], so we tested whether the loss of H3 K36 methylation (H3K36me) causes UV sensitivity
Summary
The nucleotide excision repair (NER) pathway is critically important for removing bulky, helixdistorting DNA lesions, such as UV-induced cyclobutane pyrimidine dimers (CPDs) [1,2]. NER is comprised of two subpathways: global genomic-NER (GG-NER), which repairs DNA lesions throughout the genome [3], and transcription coupled-NER (TC-NER), which repairs DNA lesions on the transcribed strand (TS) of actively transcribed genes [4,5]. These two subpathways primarily differ in the means of lesion recognition. GG-NER directly senses the helix distortion induced by bulky adducts via the DNA damage sensors XPC and UV-DDB in mammalian cells and Rad and Rad7/Rad16/Elc in Saccharomyces cerevisiae [3,6,7]. TC-NER recognizes RNA polymerase II (Pol II) stalling at a bulky, helix-distorting lesion, which triggers repair via the Cockayne syndrome B (CSB) gene in human cells, and its homolog Rad in S. cerevisiae [4,5,8]. How CSB or Rad is recruited to stalled Pol II is unknown
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