Coordinated roles of SLX4 and MutSβ in DNA repair and the maintenance of genome stability

Young, Sarah Jane; West, Stephen C.

doi:10.1080/10409238.2021.1881433

Cited by 18 publications

(22 citation statements)

References 189 publications

(217 reference statements)

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“…The SLX4 scaffold protein interacts with many proteins, including three structurespecific nucleases, MUS81-EME1, XPF-ERCC1, and SLX1. These complexes mediate a broad range of DNA transactions that promote genome stability [142]. The SLX1 structurespecific nuclease with its SLX4 co-factor cleaves a variety of branched DNA structures in vitro, it contributes to genome stability by processing branched intermediates during HR, and it promotes inter-strand crosslink repair and telomere maintenance [142][143][144].…”

Section: Other Nucleases With Known or Potential Roles In Replication...mentioning

confidence: 99%

“…These complexes mediate a broad range of DNA transactions that promote genome stability [142]. The SLX1 structurespecific nuclease with its SLX4 co-factor cleaves a variety of branched DNA structures in vitro, it contributes to genome stability by processing branched intermediates during HR, and it promotes inter-strand crosslink repair and telomere maintenance [142][143][144]. SLX4 also associates with the XPF-ERCC1 structure-specific nuclease and like SLX1-SLX4, this complex also cleaves a variety of branched DNA structures in vitro [142].…”

Section: Other Nucleases With Known or Potential Roles In Replication...mentioning

confidence: 99%

“…The SLX1 structurespecific nuclease with its SLX4 co-factor cleaves a variety of branched DNA structures in vitro, it contributes to genome stability by processing branched intermediates during HR, and it promotes inter-strand crosslink repair and telomere maintenance [142][143][144]. SLX4 also associates with the XPF-ERCC1 structure-specific nuclease and like SLX1-SLX4, this complex also cleaves a variety of branched DNA structures in vitro [142]. XPF-ERCC1 are involved in nucleotide excision repair and inter-strand crosslink repair, and it was recently shown that XPF-ERCC1 is important for DSB repair by HR when substrates form secondary structures, such as AT-rich and G-quadraplex sequences [145].…”

Section: Other Nucleases With Known or Potential Roles In Replication...mentioning

confidence: 99%

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Nucleases and Co-Factors in DNA Replication Stress Responses

Nickoloff

Sharma

Taylor

et al. 2022

DNA

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DNA replication stress is a constant threat that cells must manage to proliferate and maintain genome integrity. DNA replication stress responses, a subset of the broader DNA damage response (DDR), operate when the DNA replication machinery (replisome) is blocked or replication forks collapse during S phase. There are many sources of replication stress, such as DNA lesions caused by endogenous and exogenous agents including commonly used cancer therapeutics, and difficult-to-replicate DNA sequences comprising fragile sites, G-quadraplex DNA, hairpins at trinucleotide repeats, and telomeres. Replication stress is also a consequence of conflicts between opposing transcription and replication, and oncogenic stress which dysregulates replication origin firing and fork progression. Cells initially respond to replication stress by protecting blocked replisomes, but if the offending problem (e.g., DNA damage) is not bypassed or resolved in a timely manner, forks may be cleaved by nucleases, inducing a DNA double-strand break (DSB) and providing a means to accurately restart stalled forks via homologous recombination. However, DSBs pose their own risks to genome stability if left unrepaired or misrepaired. Here we focus on replication stress response systems, comprising DDR signaling, fork protection, and fork processing by nucleases that promote fork repair and restart. Replication stress nucleases include MUS81, EEPD1, Metnase, CtIP, MRE11, EXO1, DNA2-BLM, SLX1-SLX4, XPF-ERCC1-SLX4, Artemis, XPG, and FEN1. Replication stress factors are important in cancer etiology as suppressors of genome instability associated with oncogenic mutations, and as potential cancer therapy targets to enhance the efficacy of chemo- and radiotherapeutics.

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Section: Other Nucleases With Known or Potential Roles In Replication...mentioning

confidence: 99%

Section: Other Nucleases With Known or Potential Roles In Replication...mentioning

confidence: 99%

Section: Other Nucleases With Known or Potential Roles In Replication...mentioning

confidence: 99%

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Nucleases and Co-Factors in DNA Replication Stress Responses

Nickoloff

Sharma

Taylor

et al. 2022

DNA

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“…Likewise, murine SLX4 stimulates the activity of XPF-ERCC1 ( Hodskinson et al, 2014 ). Through these functions, SLX4 coordinates the removal of branched DNA structures that form in response to replication stress, the resolution of recombination intermediates and the repair of DNA interstrand crosslinks (for reviews, see Guervilly and Gaillard, 2018 ; Young and West, 2021 ).…”

Section: Human Slx4 Is the Scaffold For Macromolecular Structure-selective Endonuclease Complexesmentioning

confidence: 99%

“…Indeed, MSH2-MSH3 stimulated the ability of SLX1-SLX4 and SMX to cleave Holliday junctions and trinucleotide repeat loops, expanding the repertoire of DNA substrates that are cleaved by SLX4-nuclease complexes ( Young et al, 2020 ). The interplay between SLX4 and MSH2-MSH3 was reviewed recently ( Young and West, 2021 ).…”

Section: Macromolecular Slx4-complexes: New Players On the Blockmentioning

confidence: 99%

Exploring the Structures and Functions of Macromolecular SLX4-Nuclease Complexes in Genome Stability

et al. 2021

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All organisms depend on the ability of cells to accurately duplicate and segregate DNA into progeny. However, DNA is frequently damaged by factors in the environment and from within cells. One of the most dangerous lesions is a DNA double-strand break. Unrepaired breaks are a major driving force for genome instability. Cells contain sophisticated DNA repair networks to counteract the harmful effects of genotoxic agents, thus safeguarding genome integrity. Homologous recombination is a high-fidelity, template-dependent DNA repair pathway essential for the accurate repair of DNA nicks, gaps and double-strand breaks. Accurate homologous recombination depends on the ability of cells to remove branched DNA structures that form during repair, which is achieved through the opposing actions of helicases and structure-selective endonucleases. This review focuses on a structure-selective endonuclease called SLX1-SLX4 and the macromolecular endonuclease complexes that assemble on the SLX4 scaffold. First, we discuss recent developments that illuminate the structure and biochemical properties of this somewhat atypical structure-selective endonuclease. We then summarize the multifaceted roles that are fulfilled by human SLX1-SLX4 and its associated endonucleases in homologous recombination and genome stability. Finally, we discuss recent work on SLX4-binding proteins that may represent integral components of these macromolecular nuclease complexes, emphasizing the structure and function of a protein called SLX4IP.

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Multi‐omic analysis in normal colon organoids highlightsMSH4as a novel marker of defective mismatch repair in Lynch syndrome and microsatellite instability

et al. 2023

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Introduction Lynch syndrome (LS) is a hereditary condition that increases the risk of colorectal (CRC) and extracolonic cancers that exhibit microsatellite instability (MSI‐H). MSI‐H is driven by defective mismatch repair (dMMR), and approximately 15% of nonhereditary CRCs also exhibit MSI‐H. Here, we aimed to better define mechanisms underlying tumor initiation in LS and MSI‐H cancers through multi‐omic analyses of LS normal colon organoids and MSI‐H tumors. Methods Right (n = 35) and left (n = 23) colon organoids generated from normal colon biopsies at routine colonoscopy of LS and healthy individuals were subjected to Illumina EPIC array. Differentially methylated region (DMR) analysis was performed by DMRcate. RNA‐sequencing (n = 16) and bisulfite‐sequencing (n = 15) were performed on a subset of right colon organoids. CRISPR‐cas9‐mediated editing of MMR genes in colon organoids of healthy individuals was followed by quantitative PCR of MSH4. The relationship between MSH4 expression and tumor mutational burden was further explored in three independent tumor data sets. Results We identified a hypermethylated region of MSH4 in both the right and left colon organoids of LS versus healthy controls, which we validated using bisulfite‐sequencing. DMR analysis in three gastrointestinal and one endometrial data set revealed that this region was also hypermethylated in MSI‐H versus microsatellite stable (MSS) tumors. MSH4 expression was increased in colon organoids of LS versus healthy subjects and in publicly available MSI‐H versus MSS tumors across four RNA‐seq and four microarray data sets. CRISPR‐cas9 editing of MLH1 and MSH2, but not MSH6, in normal colon organoids significantly increased MSH4 expression. MSH4 expression was significantly associated with tumor mutational burden in three publicly available data sets. Conclusions Our findings implicate DNA methylation and gene expression differences of MSH4 as a marker of dMMR and as a potential novel biomarker of LS. Our study of LS colon organoids supports the hypothesis that dMMR exists in the colons of LS subjects prior to CRC.

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Coordinated roles of SLX4 and MutSβ in DNA repair and the maintenance of genome stability

Cited by 18 publications

References 189 publications

Nucleases and Co-Factors in DNA Replication Stress Responses

Nucleases and Co-Factors in DNA Replication Stress Responses

Exploring the Structures and Functions of Macromolecular SLX4-Nuclease Complexes in Genome Stability

Multi‐omic analysis in normal colon organoids highlightsMSH4as a novel marker of defective mismatch repair in Lynch syndrome and microsatellite instability

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