Control of genome stability by Slx protein complexes

Abstract

The six Saccharomyces cerevisiae SLX genes were identified in a screen for factors required for the viability of cells lacking Sgs1, a member of the RecQ helicase family involved in processing stalled replisomes and in the maintenance of genome stability. The six SLX gene products form three distinct heterodimeric complexes, and all three have catalytic activity. Slx3-Slx2 (also known as Mus81-Mms4) and Slx1-Slx4 are both heterodimeric endonucleases with a marked specificity for branched replication fork-like DNA species, whereas Slx5-Slx8 is a SUMO (small ubiquitin-related modifier)-targeted E3 ubiquitin ligase. All three complexes play important, but distinct, roles in different aspects of the cellular response to DNA damage and perturbed DNA replication. Slx4 interacts physically not only with Slx1, but also with Rad1-Rad10 [XPF (xeroderma pigmentosum complementation group F)-ERCC1 (excision repair cross-complementing 1) in humans], another structure-specific endonuclease that participates in the repair of UV-induced DNA damage and in a subpathway of recombinational DNA DSB (double-strand break) repair. Curiously, Slx4 is essential for repair of DSBs by Rad1-Rad10, but is not required for repair of UV damage. Slx4 also promotes cellular resistance to DNA-alkylating agents that block the progression of replisomes during DNA replication, by facilitating the error-free mode of lesion bypass. This does not require Slx1 or Rad1-Rad10, and so Slx4 has several distinct roles in protecting genome stability. In the present article, I provide an overview of our current understanding of the cellular roles of the Slx proteins, paying particular attention to the advances that have been made in understanding the cellular roles of Slx4. In particular, protein-protein interactions and underlying molecular mechanisms are discussed and I draw attention to the many questions that have yet to be answered.

Overlapping Roles for Yen1 and Mus81 in Cellular Holliday Junction Processing

“…Loss of Mus81 alone did not reduce JM-HJ resolution efficiency, indicating that Yen1 and Mus81 therefore possess redundant, overlapping functions required for the resolution of JM-HJ. We examined the possibility that Slx1 and/or Rad1 might be responsible for the resolution activity that persisted in the mus81⌬ yen1⌬ double mutants because Slx1 and Rad1 have overlapping substrate specificities with Mus81 in vitro (18). However, mus81⌬ yen1⌬ slx1⌬ rad1⌬ quadruple mutants were no more defective in JM-HJ resolution than the mus81⌬ yen1⌬ double mutants (Fig.…”

Chromosome Aberrations Resulting From Double-Strand DNA Breaks at a Naturally Occurring Yeast Fragile Site Composed of Inverted Ty Elements Are Independent of Mre11p and Sae2p

“…We also examined DSBs at FS2 in strains lacking various other nucleases (reviewed by Friedberg et al 2006;Mimitou and Symington 2009;Rouse 2009) in the GAL-POL1 background, including Exo1p (59-39 exonuclease and flap endonuclease), Mus81p (one subunit of a heterodimeric structure-specific nuclease), Pso2p (59-39 exonuclease), Rad1p (single-stranded endonuclease), Rad27p (59-39 exonuclease, 59 flap endonuclease), Sae2p (single-stranded exonuclease), Slx4 (59 flap endonuclease), and Yen1p (a Holliday junctioncleaving enzyme). Each mutant strain was analyzed for FS2-associated DSBs as described above.…”

Termination of Replication Stress Signaling via Concerted Action of the Slx4 Scaffold and the PP4 Phosphatase

“…As a consequence, Rad9 is displaced from DNA lesions, prohibiting further transduction of Mec1 signaling to Rad53, thus dampening the DDC. Interestingly, Slx4 has an established role as a scaffold for the coordination of structure-specific nucleases (Mullen et al 2001;Rouse 2009), so the identification of a nucleaseindependent function for Slx4 in DDC regulation suggests an intricate mechanism for the crosstalk and coordination of DDC signaling control and DNA repair.…”