Rif1 Prevents Resection of DNA Breaks and Promotes Immunoglobulin Class Switching

Virgilio, Michela Di; Callén, Elsa; Yamane, Arito; Zhang, Wenzhu; Janković, Mila; Gitlin, Alexander D.; Feldhahn, Niklas; Resch, Wolfgang; Oliveira, Thiago Y.; Chait, Brian T.; Nussenzweig, André; Casellas, Rafael; Robbiani, Davide F.; Nussenzweig, Michel C.

doi:10.1126/science.1230624

Cited by 373 publications

(395 citation statements)

References 48 publications

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“…Similarly, elevated levels of Rif1 were found in breast cancer and teratocarcinomas (Wang et al ., 2009; Li et al ., 2015). Since mammalian Rif1 participates in suppressing the HDR repair pathway in the G1 phase (Chapman et al ., 2013; Di Virgilio et al ., 2013; Escribano‐Díaz et al ., 2013; Zimmermann et al ., 2013), it was suggested that too much Rif1 drives illicit and error‐prone DSB repair, which alters the genome. However, our study shows that Rif1 can drive genomic instability in the absence of DSB repair.…”

Section: Discussionmentioning

confidence: 99%

Rif1 and Exo1 regulate the genomic instability following telomere losses

et al. 2016

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SummaryTelomere attrition is linked to cancer, diabetes, cardiovascular disease and aging. This is because telomere losses trigger further genomic modifications, culminating with loss of cell function and malignant transformation. However, factors regulating the transition from cells with short telomeres, to cells with profoundly altered genomes, are little understood. Here, we use budding yeast engineered to lack telomerase and other forms of telomere maintenance, to screen for such factors. We show that initially, different DNA damage checkpoint proteins act together with Exo1 and Mre11 nucleases, to inhibit proliferation of cells undergoing telomere attrition. However, this situation changes when survivors lacking telomeres emerge. Intriguingly, checkpoint pathways become tolerant to loss of telomeres in survivors, yet still alert to new DNA damage. We show that Rif1 is responsible for the checkpoint tolerance and proliferation of these survivors, and that is also important for proliferation of cells with a broken chromosome. In contrast, Exo1 drives extensive genomic modifications in survivors. Thus, the conserved proteins Rif1 and Exo1 are critical for survival and evolution of cells with lost telomeres.

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Section: Discussionmentioning

confidence: 99%

Rif1 and Exo1 regulate the genomic instability following telomere losses

et al. 2016

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“…Such factors are, for example, Ku70/ 80, 53BP1, and Rif1 (39)(40)(41)(42). Many classical HR factors are also implicated to be required for CSR, for example the Mre11, Rad50, and Nbs1 complex, RPA, and possibly CtIP (43)(44)(45)(46).…”

Section: Discussionmentioning

confidence: 99%

Cyclin-Dependent Kinases Regulate Ig Class Switching by Controlling Access of AID to the Switch Region

Cortizas

Verdún

et al. 2015

The Journal of Immunology

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Ig class switching requires cell proliferation and is division linked, but the detailed mechanism is unknown. By analyzing the first switching cells early in the kinetics, our analysis suggested that proliferating B cells had a very short G1 phase (<3.5 h), a total cell cycle time of ∼11 h, and that Ig class switching preferentially occurred in the late G1 or early S phase. Inhibition of cyclin-dependent kinases (CDKs) caused dramatic reduction of switching rate within 6 h. This was associated with less targeting of activation-induced cytidine deaminase (AID) to the Igh locus. Interestingly, ectopically expressed nuclear AID in HeLa cells was preferentially found in the early S phase. Furthermore, in CDK2 hypomorphic cells there was reduced nuclear AID accumulation. Thus, our data are compatible with the idea that division-linked Ig class switching is in part due to CDK2-regulated AID nuclear access at the G1/S border.

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“…Originally discovered for its role at yeast telomeres and later identified as important for controlling DNA replication, Rif1 is now known to mediate various additional chromosome stability functions, including DNA break repair pathway choice (Chapman et al 2013;Di Virgilio et al 2013;Escribano-Diaz et al 2013) and down-regulation of checkpoint activity close to telomeres (Xue et al 2011;Ribeyre and Shore 2012). All of these control mech-anisms could potentially involve regulated dephosphorylation of specific proteins.…”

Section: Evolutionary Conservation Of Pp1 Interaction Motifs In Rif1mentioning

confidence: 99%

“…It has since been demonstrated that S. cerevisiae Rif1 suppresses activation of the DNA damage checkpoint near telomeres (Xue et al 2011;Ribeyre and Shore 2012) and affects telomere replication time (Lian et al 2011). The presence of Rif1 is evolutionarily conserved, but in other eukaryotes, Rif1 has been shown to play nontelomeric roles, such as directing the pathways used in DNA double-strand break repair and DNA recombination (Chapman et al 2013;Di Virgilio et al 2013;EscribanoDiaz et al 2013). Recent studies have implicated the fission yeast (Schizosaccharomyces pombe) and mammalian Rif1 proteins in the regulation of DNA replication genome-wide.…”

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confidence: 99%

Rif1 controls DNA replication by directing Protein Phosphatase 1 to reverse Cdc7-mediated phosphorylation of the MCM complex

et al. 2014

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Initiation of eukaryotic DNA replication requires phosphorylation of the MCM complex by Dbf4-dependent kinase (DDK), composed of Cdc7 kinase and its activator, Dbf4. We report here that budding yeast Rif1 (Rap1-interacting factor 1) controls DNA replication genome-wide and describe how Rif1 opposes DDK function by directing Protein Phosphatase 1 (PP1)-mediated dephosphorylation of the MCM complex. Deleting RIF1 partially compensates for the limited DDK activity in a cdc7-1 mutant strain by allowing increased, premature phosphorylation of Mcm4. PP1 interaction motifs within the Rif1 N-terminal domain are critical for its repressive effect on replication. We confirm that Rif1 interacts with PP1 and that PP1 prevents premature Mcm4 phosphorylation. Remarkably, our results suggest that replication repression by Rif1 is itself also DDK-regulated through phosphorylation near the PP1-interacting motifs. Based on our findings, we propose that Rif1 is a novel PP1 substrate targeting subunit that counteracts DDK-mediated phosphorylation during replication. Fission yeast and mammalian Rif1 proteins have also been implicated in regulating DNA replication. Since PP1 interaction sites are evolutionarily conserved within the Rif1 sequence, it is likely that replication control by Rif1 through PP1 is a conserved mechanism.

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Rif1 Prevents Resection of DNA Breaks and Promotes Immunoglobulin Class Switching

Cited by 373 publications

References 48 publications

Rif1 and Exo1 regulate the genomic instability following telomere losses

Rif1 and Exo1 regulate the genomic instability following telomere losses

Cyclin-Dependent Kinases Regulate Ig Class Switching by Controlling Access of AID to the Switch Region

Rif1 controls DNA replication by directing Protein Phosphatase 1 to reverse Cdc7-mediated phosphorylation of the MCM complex

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