Rif1: A Conserved Regulator of DNA Replication and Repair Hijacked by Telomeres in Yeasts.

Stefano Mattarocci,Lukas Hafner,Maksym Shyian,David Shore,Aleksandra Lezaja

doi:10.3389/fgene.2016.00045

Abstract

Rap1-interacting factor 1 (Rif1) was originally identified in the budding yeast Saccharomyces cerevisiae as a telomere-binding protein that negatively regulates telomerase-mediated telomere elongation. Although this function is conserved in the distantly related fission yeast Schizosaccharomyces pombe, recent studies, both in yeasts and in metazoans, reveal that Rif1 also functions more globally, both in the temporal control of DNA replication and in DNA repair. Rif1 proteins are large and characterized by N-terminal HEAT repeats, predicted to form an elongated alpha-helical structure. In addition, all Rif1 homologs contain two short motifs, abbreviated RVxF/SILK, that are implicated in recruitment of the PP1 (yeast Glc7) phosphatase. In yeasts the RVxF/SILK domains have been shown to play a role in control of DNA replication initiation, at least in part through targeted de-phosphorylation of proteins in the pre-Replication Complex. In human cells Rif1 is recruited to DNA double-strand breaks through an interaction with 53BP1 where it counteracts DNA resection, thus promoting repair by non-homologous end-joining. This function requires the N-terminal HEAT repeat-containing domain. Interestingly, this domain is also implicated in DNA end protection at un-capped telomeres in yeast. We conclude by discussing the deployment of Rif1 at telomeres in yeasts from both an evolutionary perspective and in light of its recently discovered global functions.

Highlights

Telomeres, the ends of linear eukaryotic chromosomes, pose two fundamental problems for the cell
Chromosome ends physically resemble accidental DNA double-stranded breaks (DSBs), but must be treated differently by the cell to avoid DNA damage checkpoint activation and the genome instability caused by chromosome end fusions or translocations
In Schizosaccharomyces pombe and mammalian cells the effects of Rap1-interacting factor 1 (Rif1) on replication timing were widespread, whereas in budding yeast initial studies suggested that they might be more restricted to telomere-proximal regions, where most late-firing origins are found

Summary

Introduction

The ends of linear eukaryotic chromosomes, pose two fundamental problems for the cell. Rap1 binding alone is not sufficient for telomere length regulation by Rif1, since mutations in the conserved RVxF/SILK (involved in PP1 phosphatase binding; see Figure 1B) and the HEAT repeat domains cause telomere elongation (our unpublished results).

Results

Conclusion