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Characterization of the role of Srs2 human orthologs in triplet repeat maintenance

Triplet repeats can form hairpin structures that can lead to chromosomal instability, breakage, and fork stalling during replication. Helicases unwind these structures to maintain genome integrity. Srs2 is a PCNA interacting non‐replicative helicase and anti‐recombinase that can displace Rad51. We have previously shown that Srs2 is important in maintaining CAG repeat stability, preventing chromosome fragility at expanded repeats, and facilitating replication through repeats in yeast. Since Srs2 plays such an important role in repeat maintenance, we want to identify and characterize potential human orthologs. Two candidates are Fbh1 and Rtel. Both of these helicases have little sequence homology to Srs2 but are functional similar in that they both antagonize homologous recombination. We introduced the cDNA sequences of each of these potential orthologs into the endogenous Srs2 locus for complementation studies. We found Fbh1 and Rtel can rescue srs2Δ sensitivity to MMS and CPT, respectively. We found that Fbh1 cannot complement repeat fragility but can rescue repeat expansions that occur in srs2Δ. On the other hand Rtel partially complements both repeat fragility and instability. These results suggest that Rtel may be the closer human ortholog but in higher eukaryotes the different Srs2 functions may be divided among a number of different helicases. This research is funded by the Tufts Biology department