The Mus81 solution to resolution: generating meiotic crossovers without Holliday junctions

Hollingsworth, Nancy M.; Brill, Steven J.

doi:10.1101/gad.1165904

Cited by 233 publications

(277 citation statements)

References 61 publications

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“…It appears that meiotic crossing-over (CO) relies on different endonucleases in differents organisms. While flies rely essentially on MEI9 XPF (Yildiz et al, 2002) and fission yeast on Mus81 Cromie et al, 2006), crossing-over in budding yeast appears to rely on multiple pathways (Hollingsworth and Brill, 2004). Interestingly, large scale transcriptome studies show that the highest SLX4 mRNA levels in mouse tissues are in testes, oocytes and fertilized eggs (Su et al, 2002), consistent with the idea that SLX4 is involved in meiotic recombination in mammals.…”

Section: Slx4 and Hj Resolutionsupporting

confidence: 59%

Human SLX4 Is a Holliday Junction Resolvase Subunit that Binds Multiple DNA Repair/Recombination Endonucleases

Fekairi¹,

Scaglione²,

Chahwan³

et al. 2009

Journal of End-to-End-testing

115

204

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SummaryStructure-specific endonucleases resolve DNA secondary structures generated during DNA repair and recombination. The yeast 5′-flap endonuclease Slx1-Slx4 has received particular attention with the finding that Slx4 has Slx1-independent key functions in genome maintenance. Although Slx1 is a highly conserved protein in eukaryotes, no orthologs of Slx4 were reported other than in fungi. Here we report the identification of Slx4 orthologs in metazoa, including fly MUS312, essential for meiotic recombination, and human BTBD12, an ATM/ATR checkpoint kinase substrate. Human SLX1-SLX4 displays robust Holliday junction resolvase activity in addition to 5′-flap endonuclease activity. Depletion of SLX1 and SLX4 results in 53BP1 foci accumulation and H2AX phosphorylation as well as cellular hypersensitivity to MMS. Furthermore, we show that SLX4 binds the XPF and MUS81 subunits of the XPF-ERCC1 and MUS81-EME1 endonucleases and is required for DNA interstrand crosslink repair. We propose that SLX4 acts as a docking platform for multiple structure-specific endonucleases.

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Section: Slx4 and Hj Resolutionsupporting

confidence: 59%

Human SLX4 Is a Holliday Junction Resolvase Subunit that Binds Multiple DNA Repair/Recombination Endonucleases

Fekairi¹,

Scaglione²,

Chahwan³

et al. 2009

Journal of End-to-End-testing

115

204

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“…Recent work has indicated that gene conversions can occur via a crossover-independent pathway (reviewed in Bishop and Zickler 2004;Heyer 2004;Hollingsworth and Brill 2004). In the rec10-109 mutant, gene conversion levels at the lys7 and ura1 loci have been reported to be indistinguishable from rec10 1 levels, although data from only one experiment were reported (De Veaux and Smith 1994).…”

Section: Resultsmentioning

confidence: 99%

Linear Element-Independent Meiotic Recombination in Schizosaccharomyces pombe

et al. 2006

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Most organisms form protein-rich, linear, ladder-like structures associated with chromosomes during early meiosis, the synaptonemal complex. In Schizosaccharomyces pombe, linear elements (LinEs) are thread-like, proteinacious chromosome-associated structures that form during early meiosis. LinEs are related to axial elements, the synaptonemal complex precursors of other organisms. Previous studies have led to the suggestion that axial structures are essential to mediate meiotic recombination. Rec10 protein is a major component of S. pombe LinEs and is required for their development. In this report we study recombination in a number of rec10 mutants, one of which (rec10-155) does not form LinEs, but is predicted to encode a truncated Rec10 protein. This mutant has levels of crossing over and gene conversion substantially higher than a rec10 null mutant (rec10-175) and forms cytologically detectable Rad51 foci indicative of meiotic recombination intermediates. These data demonstrate that while Rec10 is required for meiotic recombination, substantial meiotic recombination can occur in rec10 mutants that do not form LinEs, indicating that LinEs per se are not essential for all meiotic recombination.

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“…Nevertheless, yen1Δ cells display no obvious recombination phenotypes unless combined with an mms4Δ background, and S. pombe lacks Yen1p, suggesting that in S. pombe, other nucleases (most likely Mus81p-Mms4p) must be primarily responsible for endonucleolytic resolution of recombination intermediates involving HJs (Ip et al, 2008). These data raise the question as to whether there might exist additional HJ resolvases in multicellular eukaryotes and, if so, the nature of particular biochemical pathways in which these enzymes participate (Haber and Heyer, 2001;Hollingsworth and Brill, 2004;Ciccia et al, 2008).…”

Section: Introductionmentioning

confidence: 82%

Mammalian BTBD12/SLX4 Assembles A Holliday Junction Resolvase and Is Required for DNA Repair

Svendsen¹,

Smogorzewska²,

Sowa³

et al. 2009

Journal of End-to-End-testing

199

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SummaryStructure-specific endonucleases mediate repair of DNA structures formed from replication fork collapse or during double-strand break (DSB) repair. Here we identify BTBD12 as the human ortholog of the budding yeast DNA repair factor Slx4p and D. melanogaster MUS312. Human SLX4 forms a multiprotein complex with the ERCC4(XPF)-ERCC1, MUS81-EME1, and SLX1 endonucleases, and also associates with MSH2/MSH3 mismatch repair complex, telomere binding complex TERF2(TRF2)-TERF2IP(RAP1), the protein kinase PLK1 and the uncharacterized protein C20orf94. Depletion of SLX4 causes sensitivity to mitomycin C and camptothecin, and reduces the efficiency of DSB repair in vivo. SLX4 complexes cleave 3'-flap, 5'-flap and replication fork structures; yet unlike other endonucleases associated with SLX4, the SLX1-SLX4 module promotes symmetrical cleavage of static and migrating Holliday junctions (HJs), identifying SLX1-SLX4 as a HJ resolvase. Thus, SLX4 assembles a modular tool-kit for repair of specific types of DNA lesions and is critical for cellular responses to replication fork failure.

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The Mus81 solution to resolution: generating meiotic crossovers without Holliday junctions

Cited by 233 publications

References 61 publications

Human SLX4 Is a Holliday Junction Resolvase Subunit that Binds Multiple DNA Repair/Recombination Endonucleases

Human SLX4 Is a Holliday Junction Resolvase Subunit that Binds Multiple DNA Repair/Recombination Endonucleases

Linear Element-Independent Meiotic Recombination in Schizosaccharomyces pombe

Mammalian BTBD12/SLX4 Assembles A Holliday Junction Resolvase and Is Required for DNA Repair

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