Phosphorylation of Slx4 by Mec1 and Tel1 Regulates the Single-Strand Annealing Mode of DNA Repair in Budding Yeast

Flott, Sonja; Alabert, Constance; Toh, Geraldine W.-L.; Toth, Rachel; Sugawara, Neal; Campbell, David G.; Haber, James E.; Pasero, Philippe; Rouse, John

doi:10.1128/mcb.00135-07

Cited by 91 publications

(171 citation statements)

References 60 publications

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“…Metazoan SLX4 proteins have a large N-terminal extension where we have mapped a region critical for the association of human SLX4 with the XPF subunit of the XPF-ERCC1 endonuclease ( Figure 2E). This interaction is conserved in yeast and flies (Flott et al, 2007;Ito et al, 2001) (Yildiz et al, 2002). Interestingly, this large N-terminal extension harbors at least two additional conserved functional domains not found in fungal orthologs.…”

Section: Discussion the Slx4 Family Of Proteinsmentioning

confidence: 87%

“…Despite their fundamental nature, the mechanisms that control structure-specific endonucleases remain poorly understood. Recent studies carried out in S. cerevisiae on the Slx1-Slx4 complex shed a new light on how this may be achieved in some cases (Flott et al, 2007;Flott and Rouse, 2005).…”

Section: Introductionmentioning

confidence: 99%

“…Further investigations in budding yeast uncovered Slx1-independent activities of Slx4. The SLX4 gene interacts with genes involved in error-free DNA damage bypass and Slx4 is required for resistance to DNA alkylation during S-phase (Flott et al, 2007). This is thought to involve the interaction between Slx4 and the multi-BRCT domain protein Rtt107 (Flott et al, 2007;Roberts et al, 2006;Roberts et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

“…The SLX4 gene interacts with genes involved in error-free DNA damage bypass and Slx4 is required for resistance to DNA alkylation during S-phase (Flott et al, 2007). This is thought to involve the interaction between Slx4 and the multi-BRCT domain protein Rtt107 (Flott et al, 2007;Roberts et al, 2006;Roberts et al, 2008). Rtt107 itself associates with Rtt101 CUL4 that is part of a ubiquitin (Ub) E3 ligase proposed to control protein turnover at stalled replication forks and promote replication through natural pause sites and DNA damage (Luke et al, 2006;Zaidi et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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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: Discussion the Slx4 Family Of Proteinsmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

View full text Add to dashboard Cite

show abstract

“…For example, Mec1 and Tel1 phosphorylate and activate the Sae2 nuclease as well as the Slx4 protein that serves as a scaffold for multiple cellular nucleases [54,55]. Clearly, we still need to learn much more about how the S-phase checkpoint response is able to balance the activity of cellular nucleases to preserve genome integrity at replication forks as well as stimulating DNA repair when necessary.…”

Section: Protecting Replication Forks: An 'Essential Role' Of the S-pmentioning

confidence: 99%

Surviving chromosome replication: the many roles of the S-phase checkpoint pathway

Labib

Piccoli

2011

Phil. Trans. R. Soc. B

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Checkpoints were originally identified as signalling pathways that delay mitosis in response to DNA damage or defects in chromosome replication, allowing time for DNA repair to occur. The ATR (ataxia-and rad-related) and ATM (ataxia-mutated) protein kinases are recruited to defective replication forks or to sites of DNA damage, and are thought to initiate the DNA damage response in all eukaryotes. In addition to delaying cell cycle progression, however, the S-phase checkpoint pathway also controls chromosome replication and DNA repair pathways in a highly complex fashion, in order to preserve genome integrity. Much of our understanding of this regulation has come from studies of yeasts, in which the best-characterized targets are the stimulation of ribonucleotide reductase activity by multiple mechanisms, and the inhibition of new initiation events at later origins of DNA replication. In addition, however, the S-phase checkpoint also plays a more enigmatic and apparently critical role in preserving the functional integrity of defective replication forks, by mechanisms that are still understood poorly. This review considers some of the key experiments that have led to our current understanding of this highly complex pathway.

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A tale of tails: insights into the coordination of 3′ end processing during homologous recombination

Lyndaker

Alani

2009

BioEssays

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SummaryEukaryotic genomes harbor a large number of homologous repeat sequences that are capable of recombining at high frequency. Their potential to disrupt genome stability highlights the need to understand how homologous recombination processes are coordinated. The S. cerevisiae Rad1-Rad10 endonuclease performs an essential role in recombination between repeated sequences by processing 3′ single-stranded intermediates formed during single-strand annealing and gene conversion events. Several recent studies have focused on factors involved in Rad1-Rad10-dependent removal of 3′ nonhomologous tails during homologous recombination, including Msh2-Msh3, Slx4, and the newly identified Saw1 protein (1-4). In addition, these studies suggest mechanisms for how DNA repair is coordinated by the DNA damage checkpoint machinery (1). This review aims to integrate these new findings with previous work to create a comprehensive model for how DNA repair and checkpoint factors act in concert to process 3′ nonhomologous tail intermediates that arise during homologous recombination. KeywordsRad1-Rad10; Saw1; Slx4; Msh2-Msh3; nonhomologous tail Homologous stretches of DNA sequences scattered throughout the genome are a threat to genome stability because of their potential to recombine. It is estimated that nearly half of the human genome consists of repetitive DNA (5,6), and genome rearrangements caused by recombination between repeats are known to contribute to a variety of human diseases, including many cancers (7)(8)(9). Repetitive sequences such as Alu elements are particularly susceptible to non-conservative homologous recombination via single-strand annealing (SSA), which results in the deletion of sequences located between the repeats (10-12). The abundance of such sequences in the human genome underscores the need for a comprehensive understanding of the homologous recombination processes that act on them.SSA is a major recombination pathway for repairing spontaneous and induced double-strand breaks (DSBs) that arise between repeated sequences (10,13,14). During SSA in S. cerevisiae, DSBs are resected 5′ to 3′ to reveal single-stranded homologous sequences ( Figure 1). Following Rad52-and Rad59-dependent annealing of the homologous sequences, the 3′ single-stranded DNA ends are nonhomologous to the new flanking regions, and must be cleaved in order to complete repair of the broken strands. The Rad1-Rad10 endonuclease and Msh2-Msh3 mismatch recognition complex are required for cleaving 3′ single-stranded nonhomologous tails on either side of the annealed region (15)(16)(17)(18)(19) NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript been removed, SSA is completed by DNA synthesis initiated off of the newly cleaved 3′ ends followed by ligation (reviewed in 10).Rad1-Rad10 is a structure-specific endonuclease that functions in both nucleotide excision repair (NER) and homologous recombination (10,11,19,20). The significance of the role of Rad1-Rad10 in recombination is demonstrated by the severe developm...

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Phosphorylation of Slx4 by Mec1 and Tel1 Regulates the Single-Strand Annealing Mode of DNA Repair in Budding Yeast

Cited by 91 publications

References 60 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

Surviving chromosome replication: the many roles of the S-phase checkpoint pathway

A tale of tails: insights into the coordination of 3′ end processing during homologous recombination

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