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ASH1L methyltransferase deposits H3K4me3 and FACT for damage verification in nucleotide excision repair [ATAC-Seq]

ABSTRACT: To recognize DNA damage, nucleotide excision repair (NER) deploys a multipart mechanism by which the XPC sensor detects helical distortions followed by engagement of TFIIH for lesion verification. Accessory players ensure that this factor handover takes place on chromatin where DNA is wrapped around histones. We show that the histone methyltransferase ASH1L, once activated by MRG15, accelerates global-genome NER activity. Upon UV irradiation, ASH1L deposits H3K4me3 marks all over the genome (except in gene promoters), thus priming chromatin for relocations of XPC from native to damaged DNA. ASH1L further recruits the histone chaperone FACT to UV lesions. In the absence of ASH1L, MRG15 or FACT, XPC persists on damaged DNA without being able to deliver lesions to the TFIIH verifier. We conclude that ASH1L implements repair hotspots whose H3K4me3 and FACT occupancy confers an active promoter-like code and organization of histones that make DNA damage verifiable by the NER machinery.

ORGANISM(S): Homo sapiens

PROVIDER: GSE227007 | GEO | 2023/06/08

REPOSITORIES: GEO

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ASH1L methyltransferase deposits H3K4me3 and FACT for damage verification in nucleotide excision repair [ChIP-Seq]

Project description:To recognize DNA damage, nucleotide excision repair (NER) deploys a multipart mechanism by which the XPC sensor detects helical distortions followed by engagement of TFIIH for lesion verification. Accessory players ensure that this factor handover takes place on chromatin where DNA is wrapped around histones. We show that the histone methyltransferase ASH1L, once activated by MRG15, accelerates global-genome NER activity. Upon UV irradiation, ASH1L deposits H3K4me3 marks all over the genome (except in gene promoters), thus priming chromatin for relocations of XPC from native to damaged DNA. ASH1L further recruits the histone chaperone FACT to UV lesions. In the absence of ASH1L, MRG15 or FACT, XPC persists on damaged DNA without being able to deliver lesions to the TFIIH verifier. We conclude that ASH1L implements repair hotspots whose H3K4me3 and FACT occupancy confers an active promoter-like code and organization of histones that make DNA damage verifiable by the NER machinery.

2023-06-08 | GSE214182 | GEO

ASH1L methyltransferase deposits H3K4me3 and FACT for damage verification in nucleotide excision repair [ChIP-Seq ASH1L-CTD]

2023-06-08 | GSE227008 | GEO

Whole genome expression data from formalin-fixed parrafin embedded (FFPE) primary and metastatic melanomas

Project description:The dominant genetic signature found in melanoma is C to T mutations due to UV radiation. Nucleotide excision repair (NER) recognises and repairs UV-induced DNA damage. We aimed to determine the effect of high UV exposure on the melanoma transcriptome and key NER transcripts in melanoma tumours in association with clinical and genetic features of the disease. 196 primary or metastatic melanomas were utilised for this study. Solar elastosis and transcriptome data was collected. mRNA transcript levels of NER components XPC, DDB1 and DDB2 were quantified and compared to clinical parameters. Solar elastosis negatively correlated with Breslow thickness (-0.251, p=0.017) and was significantly lower in BRAFV600E melanomas. Lower XPC expression was associated with BRAFV600E and NRASQ61R mutations, earlier age of diagnosis and poorer survival. Transcriptome profiling identified an over-representation of DNA repair processes in high vs low solar elastosis. Further analysis revealed DNA repair and kinase activity related transcripts in the low XPC melanomas. XPC deficiency is associated with the presence of kinase mutations and an aggressive disease phenotype, both of which result from the hypermutability of melanoma.

2016-12-31 | GSE59455 | GEO

Structural basis of TFIIH activation for nucleotide excision repair

Project description:Nucleotide excision repair (NER) is the major DNA repair pathway that removes UV-induced and bulky DNA lesions. There is currently no structure of NER intermediates, which form around the large multisubunit transcription factor IIH (TFIIH). Here we report the cryo-EM structure of an NER intermediate containing TFIIH and the NER factor XPA. Compared to its transcription conformation, the TFIIH structure is rearranged such that its ATPase subunits XPB and XPD bind double- and single-stranded DNA, consistent with their translocase and helicase activities, respectively. XPA releases the inhibitory kinase module of TFIIH, displaces a ‘plug’ element from the DNA-binding pore in XPD, and together with the NER factor XPG stimulates XPD activity. Our results explain how TFIIH is switched from a transcription to a repair factor, and provide the basis for a mechanistic analysis of the NER pathway.

2019-07-02 | PXD013947 | Pride

Structure of TFIIK for phosphorylation of CTD of RNA polymerase II

Project description:TFIIH is a 10-protein complex that is conserved through out eukaryotes. TFIIH has two primary cellular functions: transcription initiation and nucleotide excision repair (NER). In transcription initiation, TFIIH acts as a structural scaffold, phosphorylates the RNA polymerase II (pol II) C-terminal domain (CTD) and translocates promoter DNA through the pol II active site to facilitate start site selection. In NER, again is a structural scaffold, opens a bubble around damaged DNA and scans the damaged strand for bulky lesions. In yeast (Saccharomyces cerevisiae), TFIIH is composed of the two helicases Ssl2 and Rad3, the scaffolding subunits Tfb1, Tfb2, Tfb4 and Ssl1 and the kinase subunits Kin28, Ccl1 and Tfb3.

2021-07-07 | PXD021211 | Pride

Structure of TFIIH/Rad4-Rad23-Rad33 in damaged DNA opening in Nucleotide Excision Repair

Project description:TFIIH is a 10-protein complex that is conserved throughout eukaryotes. TFIIH has two primary cellular functions: transcription initiation and nucleotide excision repair (NER). NER in eukaryotes begins by recognition of a bulky lesion by the obligate dimer Rad4-Rad23. This is followed closely by the recruitment of TFIIH which is a structural scaffold, opens a bubble around damaged DNA and scans the damaged strand for bulky lesions. This facilitates the recruitment of two exonucleases which excise the damages strand before an undamaged complement is synthesize. In yeast (Saccharomyces cerevisiae), TFIIH is composed of the two helicases Ssl2 and Rad3, the scaffolding subunits Tfb1, Tfb2, Tfb4 and Ssl1 and the kinase subunits Kin28, Ccl1 and Tfb3, though these later 3 are dispensable for NER.

2021-07-07 | PXD021212 | Pride

CPD-seq mapping of transcription-coupled DNA repair in yeast

Project description:Transcription-coupled nucleotide excision repair (TC-NER) is an important DNA repair mechanism that responds to RNA polymerase (RNAP) stalling and removes DNA lesions from transcribed genes. Activation of TC-NER requires specific factors, such as human Cockayne syndrome group B (CSB) protein or its yeast homolog Rad26. Mutations in CSB are associated with the severe neurological disorder Cockayne syndrome. However, the genome-wide role of CSB/Rad26 in TC-NER, particularly in the context of chromatin organization, is not fully understood. Here we used single-nucleotide resolution UV damage mapping data to investigate the genome-wide function of Rad26 in TC-NER. Our data shows that Rad26 is critical for TC-NER in transcribed regions downstream of the first (+1) nucleosome; however, Rad26 is largely dispensable for TC-NER in the +1 nucleosome. We further show that the Rad26-independent TC-NER in the +1 nucleosome is correlated with high occupancy of the transcription initiation/repair factor TFIIH. Downstream of the +1 nucleosome, the combination of low TFIIH occupancy and high occupancy of the transcription elongation factor Spt4/Spt5 suppresses TC-NER when Rad26 is dysfunctional. Deletion of SPT4 significantly restores TC-NER in the downstream nucleosomes in a rad26∆ mutant. Collectively, these data indicate that the requirement for Rad26 in TC-NER is modulated by the distribution of TFIIH and Spt4/Spt5, and Rad26 mainly functions in the downstream nucleosomes to remove TC-NER suppression by Spt4/Spt5.

2020-06-30 | GSE145911 | GEO

An XPC-PARP axis links ALC1-mediated chromatin remodeling to global genome DNA damage repair

Project description:Cells employ global genome DNA damage repair (GGR) to eliminate a broad spectrum of DNA lesions, including those induced by UV light. The lesion-recognition factor XPC initiates repair of helix-distorting DNA lesions, but binds inefficiently to lesions that cause poor helix distortion. How such difficult-to-repair lesions are detected in chromatin is unknown. Here, we identify the poly-(ADP-ribose) polymerases PARP1 and PARP2 as constitutive interactors of XPC. The close interaction between these proteins results in the PARylation of XPC at UV lesions, and an XPC-dependent stimulation of the poly-(ADP-ribose) response, which facilitates the recruitment of the poly-(ADP-ribose)-dependent chromatin remodeler ALC1. Both ALC1 and in particular PARP2 are required for the efficient clearing of difficult-to-repair DNA lesions. Our study offers key insights into the molecular mechanisms of GGR by revealing a molecular bookmarking system, which primes chromatin containing difficult-to-repair DNA lesions for efficient repair.

2022-07-15 | PXD025226 | Pride

The yeast GG-NER complex evicts histone H2A.Z-containing barrier nucleosomes from CID boundaries during DNA repair

Project description:Background: Repair of DNA damage requires chromatin remodeling to permit removal of the lesions. How nucleosomes are remodelled to initiate repair of DNA damage remains largely unknown. Here, we describe how chromatin is altered during repair of UV-induced DNA damage at the level of the linear organisation of nucleosomes. Results: Using MNase-seq, we identified a subset of nucleosomes in the genome that are remodelled in UV-damaged wild-type yeast cells. We mapped the genomic location of these nucleosomes, showing that they contain the histone variant H2A.Z. The remodelling observed is consistent with histone exchange or eviction at these positions. This depends on the yeast SWI/SNF global genome nucleotide excision repair (GG-NER) chromatin-remodelling complex. Remarkably, we found that in the absence of DNA damage, the GG-NER complex occupies chromatin at nucleosome free regions separating adjacent nucleosomes. This establishes the nucleosome structure at these genomic locations, which we refer to as GG-NER complex binding sites (GCBS’s). We observed that these sites are frequently located precisely at certain boundary regions that delineate chromasomally interacting domains (CIDs). These boundaries define chromosomal domains of higher-order nucleosome-nucleosome interaction. We demonstrate that the GG-NER complex redistributes following remodelling of these nucleosomes after DNA damage taking up genomic positions located within the CIDs. This permits the efficient removal of DNA damage at these sites. Conclusions: We argue that organising DNA repair in the genome as described may define origins of DNA repair that greatly reduces the genomic search space for DNA damage recognition, thus ensuring the efficient repair of damage in chromatin.

2018-12-06 | E-MTAB-6569 | biostudies-arrayexpress

Global Genome-Nucleotide Excision Repair is Organised into Domains Promoting Efficient DNA Repair in Chromatin

Project description:The rates at which lesions are removed by DNA repair can vary widely throughout the genome with important implications for genomic stability. We measured the distribution of nucleotide excision repair (NER) rates for UV induced lesions throughout the yeast genome. By plotting these repair rates in relation to all ORFs and their associated flanking sequences, we reveal that in normal cells, genomic repair rates display a distinctive pattern, suggesting that DNA repair is highly organised within the genome. We compared genome-wide DNA repair rates in wild type and in RAD16 deleted cells, which are defective in the global genome-NER (GG-NER) sub-pathway, demonstrating how this alters the normalâ¨distribution of NER rates throughout the genome. We examine the genomic locations of global genome NER factor binding in chromatin before and after UV irradiation, and reveal that GG-NER is organized and initiated from specific locations. By controlling the chromatin occupancy of the histone acetyl transferase Gcn5, the GG-NER complex regulates the histone H3 acetylation status and chromatin structure in the vicinity of these genomic sites to promote the efficient DNA repair of UV induced lesions. This demonstrates that chromatin remodeling during the GG-NER process is organized into domains in the genome. Importantly, we demonstrate that deleting the histone modifier GCN5, an accessory factor required for chromatin remodeling during GG-NER, significantly alters the genomic distribution of NER rates. These observations could have important implications for the effect of histone and chromatin modifiers on the distribution of genomic mutations acquired throughout the genome.

2016-07-21 | E-MTAB-4641 | biostudies-arrayexpress

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