Localization-Dependent and -Independent Roles of SLX4 in Regulating Telomeres

Abstract

SummarySLX4, a scaffold for structure-specific DNA repair nucleases, is important for several types of DNA repair. Many repair proteins bind to sites of DNA damage, resulting in subnuclear “foci,” but SLX4 forms foci in human cells even without DNA damage. Using several approaches, we show that most, but not all, SLX4 foci localize to telomeres in a range of human cell lines irrespective of the mechanisms used to maintain telomere length. The SLX1 Holliday-junction-processing enzyme is recruited to telomeres by SLX4, and SLX4, in turn, is recruited by a motif that binds to the shelterin subunit TRF2 directly. We also show that TRF2-dependent recruitment of SLX4 prevents telomere damage. Furthermore, SLX4 prevents telomere lengthening and fragility in a manner that appears to be independent of telomere association. These findings reveal that SLX4 plays multiple roles in regulating telomere homeostasis.

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

“…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).…”

Holliday junction processing enzymes as guardians of genome stability

“…SLX4 interacts with the shelterin components TRF2 and RAP1 and colocalizes with TRF2 in distinct nuclear foci containing telomeric DNA [12,75,76]. Telomeric recruitment of SLX4 is dependent on SLX4-TRF2 interaction, but is independent of the cell-cycle stage, the presence or absence of exogenous DNA damage, and the mechanism of telomere maintenance [75,76].…”

“…Telomeric recruitment of SLX4 is dependent on SLX4-TRF2 interaction, but is independent of the cell-cycle stage, the presence or absence of exogenous DNA damage, and the mechanism of telomere maintenance [75,76]. The absence of SLX4 from telomeres results in increased telomere dysfunction-induced foci (TIFs), implicating SLX4 in telomere damage avoidance [75].…”

The SLX4 Complex Is a SUMO E3 Ligase that Impacts on Replication Stress Outcome and Genome Stability

“…Importantly, BLM and the FA pathway contribute to the stability of genomic loci that are challenging to replicate, such as common fragile sites (CFSs) (Chan et al, 2009;Naim and Rosselli, 2009). SLX4 is also required for telomere stability through its direct interactions with TRF2, SLX1, and XPF-ERCC1 (Vannier et al, 2012;Wan et al, 2013;Wilson et al, 2013). Although human SLX4 sits at the crossroads of genome maintenance and cellcycle control mechanisms, little is known as to how its various functions and those of its different partners are orchestrated.…”