SLX4 Assembles a Telomere Maintenance Toolkit by Bridging Multiple Endonucleases with Telomeres

Wan, Biao; Yin, Jinhu; Horvath, Kent; Sarkar, Jaya; Chen, Yong; Wu, Jian; Wan, Ke; Lü, Jian; Gu, Peili; Yu, Eun Young; Lue, Neal F.; Chang, Sandy; Liu, Yie; Lei, Ming

doi:10.1016/j.celrep.2013.08.017

Cited by 106 publications

(192 citation statements)

References 31 publications

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“…It is not known whether mammalian cells deficient for the MUS81 and GEN1 nucleases show loss of telomeric repeats. However, depletion of MUS81 in ALT (alternative lengthening of telomeres) cells, in which telomeres are maintained by HR, results in reduction of specific telomere recombination, telomere loss, and proliferation arrest (Zeng et al, 2009;Wan et al, 2013;Wilson et al, 2013). In contrast, no telomere loss was observed in telomerasepositive cells depleted of MUS81 (Pepe and West, 2014).…”

Section: Discussionmentioning

confidence: 75%

The Structure-Specific Endonucleases MUS81 and SEND1 Are Essential for Telomere Stability in Arabidopsis

et al. 2015

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Structure-specific endonucleases act to repair potentially toxic structures produced by recombination and DNA replication, ensuring proper segregation of the genetic material to daughter cells during mitosis and meiosis. Arabidopsis thaliana has two putative homologs of the resolvase (structure-specific endonuclease): GEN1/Yen1. Knockout of resolvase genes GEN1 and SEND1, individually or together, has no detectable effect on growth, fertility, or sensitivity to DNA damage. However, combined absence of the endonucleases MUS81 and SEND1 results in severe developmental defects, spontaneous cell death, and genome instability. A similar effect is not seen in mus81 gen1 plants, which develop normally and are fertile. Absence of RAD51 does not rescue mus81 send1, pointing to roles of these proteins in DNA replication rather than DNA break repair. The enrichment of S-phase histone g-H2AX foci and a striking loss of telomeric DNA in mus81 send1 further support this interpretation. SEND1 has at most a minor role in resolution of the Holliday junction but acts as an essential backup to MUS81 for resolution of toxic replication structures to ensure genome stability and to maintain telomere integrity.

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Section: Discussionmentioning

confidence: 75%

The Structure-Specific Endonucleases MUS81 and SEND1 Are Essential for Telomere Stability in Arabidopsis

et al. 2015

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“…[30][31][32] It has been also reported that As 2 O 3 treatment leads to damage to telomeres. 33 We then studied whether Mus81 sumoylation was involved in DNA damage responses after exposure to metal toxins including arsenic and chromium .…”

Section: Compromised Dna Damage Response In Cells Expressing Mus81-5rmentioning

confidence: 99%

Arsenic-induced sumoylation of Mus81 is involved in regulating genomic stability

Yang

et al. 2017

Cell Cycle

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Chronic environmental exposure to metal toxicants such as chromium and arsenic is closely related to the development of several types of common cancers. Genetic and epigenetic studies in the past decade reveal that post-translational modifications of histones play a role in metal carcinogenesis. However, exact molecular mechanisms of metal carcinogenesis remain to be elucidated. In this study we found that As 2 O 3 , an environmental metal toxicant, upregulated overall modifications of many cellular proteins by SUMO2/3. Sumoylated proteins from arsenic-treated cells constitutively expressing His 6 -SUMO2 were pulled down by Ni-IDA resin under denaturing conditions. Mass spectrometric analysis revealed over 100 proteins that were potentially modified by sumoylation. Mus81, a DNA endonuclease involved in homologous recombination repair, was among the identified proteins whose sumoylation was increased after treatment with As 2 O 3. We further showed that K10 and K524 were 2 lysine residues essential for Mus81 sumoylation. Moreover, we demonstrated that Mus81 sumoylation is important for normal mitotic chromosome congression and that cells expressing SUMO-resistant Mus81 mutants displayed compromised DNA damage responses after exposure to metal toxins such as Cr(VI) and arsenic.

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“…Slx4 and Saw1 are proposed to function as scaffolds that assemble XPF and other structure-specific endonucleases (Lyndaker and Alani 2009;Kashiyama et al 2013;Li et al 2013;Wan et al 2013). In contrast to budding yeast (Flott et al 2007;Li et al 2008), neither slx4Δ nor saw1Δ is sensitive to UV or MMS in fission yeast (Figure S3 and (Coulon et al 2006).…”

Section: Rad16-249 Has Genetic Interactions With Other Dna Damage Repmentioning

confidence: 99%

“…Finally, we observed sensitivity to hydroxyurea (HU) in rad16-249 and rhp14Δ mutants, but again not in rad13Δ. HU causes fork stalling due to nucleotide depletion, and restart occurs via recombination-based mechanisms (Meister et al 2007;Lambert et al 2010;Sabatinos et al 2012).Slx4 and Saw1 are proposed to function as scaffolds that assemble XPF and other structure-specific endonucleases (Lyndaker and Alani 2009;Kashiyama et al 2013;Li et al 2013;Wan et al 2013). In contrast to budding yeast (Flott et al 2007;Li et al 2008), neither slx4Δ nor saw1Δ is sensitive to UV or MMS in fission yeast (Figure S3 and (Coulon et al 2006).…”

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confidence: 99%

Increased Meiotic Crossovers and Reduced Genome Stability in Absence of Schizosaccharomyces pombe Rad16 (XPF)

Mastro¹,

Forsburg

2014

Genetics

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Schizosaccharomyces pombe Rad16 is the ortholog of the XPF structure-specific endonuclease, which is required for nucleotide excision repair and implicated in the single strand annealing mechanism of recombination. We show that Rad16 is important for proper completion of meiosis. In its absence, cells suffer reduced spore viability and abnormal chromosome segregation with evidence for fragmentation. Recombination between homologous chromosomes is increased, while recombination within sister chromatids is reduced, suggesting that Rad16 is not required for typical homolog crossovers but influences the balance of recombination between the homolog and the sister. In vegetative cells, rad16 mutants show evidence for genome instability. Similar phenotypes are associated with mutants affecting Rhp14 XPA but are independent of other nucleotide excision repair proteins such as Rad13 XPG . Thus, the XPF/XPA module of the nucleotide excision repair pathway is incorporated into multiple aspects of genome maintenance even in the absence of external DNA damage.T HE XPF/ERCC1 protein complex is one of several structurespecific endonucleases that function broadly as resolvases in the repair of damaged DNA (Schwartz and Heyer 2011). Rad16/Swi9 is the fission yeast ortholog of endonuclease XPF, which forms a complex with Swi10/Rad23 (ERCC1) (Carr et al. 1994). XPF has a conserved role in nucleotide excision repair (NER) to remove UV-induced lesions in the DNA (Camenisch et al. 2006;Gregg et al. 2011). In humans, mutation of XPF is associated with xeroderma pigmentosum (XP), which causes sun sensitivity and high rates of skin cancer, as well as premature aging and neurological disorders (Camenisch et al. 2006;Gregg et al. 2011). Recent studies suggest XPF mutations are also associated with Fanconi anemia (FA), which requires repair of interstrand crosslinks (ICLs) (Bogliolo et al. 2013;Kashiyama et al. 2013). The canonical model for NER suggests that upon recognition of helix-distorting lesions, the DNA is unwound to form a bubble around the damage. XPA (SpRhp14) loads XPF (SpRad16) and ERCC1 (SpSwi10); XPF cleaves at the 59 end of the bubble while XPG (SpRad13), another endonuclease, cleaves at the 39 end to remove the offending segment (Fagbemi et al. 2011;Schwartz and Heyer 2011). Thus, Schizosaccharomyces pombe rad16 mutants show a decrease in (6-4) photoproduct excision (McCready et al. 1993;Carr et al. 1994).Consistent with these clinical effects, XPF is implicated in multiple mechanisms of genome maintenance (Paques and Haber 1997;Gregg et al. 2011;Schwartz and Heyer 2011). XPF is required for single strand annealing (SSA), a form of double strand break (DSB) repair distinct from typical homologous recombination (HR) (Ma et al. 2003;Kass and Jasin 2010). This occurs when short regions of homology exposed by resection are able to pair, leaving nonhomologous 39 overhangs as substrates for XPF cleavage. In budding yeast, recruitment of ScRad1 XPF and ScRad10 ERCC1 in this pathway depends on interactions with other pro...

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SLX4 Assembles a Telomere Maintenance Toolkit by Bridging Multiple Endonucleases with Telomeres

Cited by 106 publications

References 31 publications

The Structure-Specific Endonucleases MUS81 and SEND1 Are Essential for Telomere Stability in Arabidopsis

The Structure-Specific Endonucleases MUS81 and SEND1 Are Essential for Telomere Stability in Arabidopsis

Arsenic-induced sumoylation of Mus81 is involved in regulating genomic stability

Increased Meiotic Crossovers and Reduced Genome Stability in Absence of Schizosaccharomyces pombe Rad16 (XPF)

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