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. 2016 Mar 30:7:45.
doi: 10.3389/fgene.2016.00045. eCollection 2016.

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

Stefano Mattarocci  1 , Lukas Hafner  1 , Aleksandra Lezaja  1 , Maksym Shyian  1 , David Shore  1
Affiliations

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

Stefano Mattarocci et al. Front Genet. .

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.

Keywords: DNA recombination; DNA repair; DNA replication timing; Rap1; Rif1; telomere; telomere capping.

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Figures

FIGURE 1
FIGURE 1
(A) Shelterin complexes assembled on telomere-repeat sequences in budding yeast (Saccharomyces cerevisiae), fission yeast (Schizosaccharomyces pombe) and human cells. Proteins discussed here are highlighted in color. It should be noted that Schizosaccharomyces pombe and human also contain a CST complex involved in DNA replication at telomeres and, at least in humans, genome-wide. (B) Schematic representation of Rif1 motif structure in human, fly and budding yeast, with functional properties for the Saccharomyces cerevisiae protein indicated below. The yellow oval represents a region of homology to the alpha-CTD of bacterial polymerases that in hRif1 has been shown to have DNA-binding activity (Xu et al., 2010).
FIGURE 2
FIGURE 2
(A) Schematic representation of Rif1 function at budding yeast telomeres (left), replication origins in yeasts (center) and double-strand breaks in mammalian cells (right). See text for details. (B) Conservation of Rif1 functions across species. Filled squares indicate that the function is present, according to at least one report; open squares indicate evidence for absence of function in at least one report; “?” indicates that the function has not been tested for in that organism. Note that for mammals, a Rif1 role in silencing, telomere length regulation and telomere capping has been examined only in mouse ES cells (Dan et al., 2014). (C) Conservation of Rif1 and Rap1 domains in yeasts. Filled square indicates presence and open square absence of indicated domain or motif.
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