Protein Phosphatase 1 Recruitment by Rif1 Regulates DNA Replication Origin Firing by Counteracting DDK Activity

Davé, Anoushka; Cooley, Carol; Garg, Mansi; Bianchi, Alessandro

doi:10.1016/j.celrep.2014.02.019

Cited by 166 publications

(229 citation statements)

References 40 publications

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“…It was recently reported that Rif1 can erase Mcm2-7 phosphorylation by recruiting the protein phosphatase PP1 to the replisome. Therefore, rif1Δ suppressed a cdc7-1 mutation at 30°C and restored cell growth at that temperature (54,57,58). To investigate whether there was a correspondence between suppression of DDK mutants by rif1Δ and restoration of PFA, we first performed growth analysis and confirmed that rif1Δ could suppress a cdc7-1 mutation at 30°C but not at 37°C (Fig.…”

Section: Deletion Of the Inhibitory Domain In The N-terminal Region Omentioning

confidence: 99%

Phosphorylation of CMG helicase and Tof1 is required for programmed fork arrest

Bastia

Srivastava

Zaman

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Several important physiological transactions, including control of replicative life span (RLS), prevention of collision between replication and transcription, and cellular differentiation, require programmed replication fork arrest (PFA). However, a general mechanism of PFA has remained elusive. We previously showed that the Tof1–Csm3 fork protection complex is essential for PFA by antagonizing the Rrm3 helicase that displaces nonhistone protein barriers that impede fork progression. Here we show that mutations of Dbf4-dependent kinase (DDK) of Saccharomyces cerevisiae, but not other DNA replication factors, greatly reduced PFA at replication fork barriers in the spacer regions of the ribosomal DNA array. A key target of DDK is the mini chromosome maintenance (Mcm) 2–7 complex, which is known to require phosphorylation by DDK to form an active CMG [Cdc45 (cell division cycle gene 45), Mcm2–7, GINS (Go, Ichi, Ni, and San)] helicase. In vivo experiments showed that mutational inactivation of DDK caused release of Tof1 from the chromatin fractions. In vitro binding experiments confirmed that CMG and/or Mcm2–7 had to be phosphorylated for binding to phospho-Tof1–Csm3 but not to its dephosphorylated form. Suppressor mutations that bypass the requirement for Mcm2–7 phosphorylation by DDK restored PFA in the absence of the kinase. Retention of Tof1 in the chromatin fraction and PFA in vivo was promoted by the suppressor mcm5-bob1, which bypassed DDK requirement, indicating that under this condition a kinase other than DDK catalyzed the phosphorylation of Tof1. We propose that phosphorylation regulates the recruitment and retention of Tof1–Csm3 by the replisome and that this complex antagonizes the Rrm3 helicase, thereby promoting PFA, by preserving the integrity of the Fob1–Ter complex.

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Section: Deletion Of the Inhibitory Domain In The N-terminal Region Omentioning

confidence: 99%

Phosphorylation of CMG helicase and Tof1 is required for programmed fork arrest

Bastia

Srivastava

Zaman

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…In budding yeast, proximity to telomeric heterochromatin is both necessary and sufficient to delay origin firing (Ferguson and Fangman 1992). This effect is regulated by Rif1-dependent recruitment of protein phosphatase I, which may antagonize origin activation by the cyclin-and DBF4-dependent kinases (Lian et al 2011;Davé et al 2014;Hiraga et al 2014;Mattarocci et al 2014). Chromatin structure-in particular, histone deacetylation by Sir2 and Rpd3-also affects the timing of nontelomeric origins (Knott et al 2009(Knott et al , 2012Peace et al 2014;Yoshida et al 2014).…”

mentioning

confidence: 99%

Replication timing is regulated by the number of MCMs loaded at origins

et al. 2015

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Replication timing is a crucial aspect of genome regulation that is strongly correlated with chromatin structure, gene expression, DNA repair, and genome evolution. Replication timing is determined by the timing of replication origin firing, which involves activation of MCM helicase complexes loaded at replication origins. Nonetheless, how the timing of such origin firing is regulated remains mysterious. Here, we show that the number of MCMs loaded at origins regulates replication timing. We show for the first time in vivo that multiple MCMs are loaded at origins. Because early origins have more MCMs loaded, they are, on average, more likely to fire early in S phase. Our results provide a mechanistic explanation for the observed heterogeneity in origin firing and help to explain how defined replication timing profiles emerge from stochastic origin firing. These results establish a framework in which further mechanistic studies on replication timing, such as the strong effect of heterochromatin, can be pursued.

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“…The other possibility is that Sgo2 acts at the subtelomeres independently of the knobs. As described in Masai et al's review, the telomere-binding protein Rif1 regulates the replication timing of late origins by interacting with PP1 phosphatase to counteract the action of Dbf4-dependent kinase (DDK) at the initiation step of replication (Davé et al, 2014;Hiraga et al, 2014;Mattarocci et al, 2014). Interestingly, Sgo1 forms a complex with PP2A phosphatase to protect cohesins in S. pombe, S. cerevisiae and mammals (Kitajima et al, 2006;Riedel et al, 2006;Tang et al, 2006;, and human Sgo2 also interacts with PP2A for the protection of cohesion (Tanno et al, 2010).…”

Section: Sgo2 Represses Transcription Of Subtelomeric Genesmentioning

confidence: 99%

Unexpected roles of a shugoshin protein at subtelomeres

Kanoh

2017

Genes Genet. Syst.

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A chromosome is composed of structurally and functionally distinct domains. Telomeres, which are located at the ends of linear chromosomes, play crucial roles in genome stability. Although substantial knowledge of telomeres has been accumulated, the regulation and function of subtelomeres, which are the domains adjacent to telomeres, remain largely unknown. In this review, I describe recent discoveries about the multiple roles of a shugoshin family protein, Sgo2, which is localized at centromeres in mitosis and contributes to precise chromosome segregation, in defining chromatin structure and functions of the subtelomeres in fission yeast. Sgo2 becomes enriched at the subtelomeres, particularly during G 2 phase, and is essential for the formation of a highly condensed subtelomeric chromatin body called the knob. Furthermore, Sgo2 maintains the expression levels of subtelomeric genes and the timing of DNA replication at subtelomeric late origins.

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Protein Phosphatase 1 Recruitment by Rif1 Regulates DNA Replication Origin Firing by Counteracting DDK Activity

Cited by 166 publications

References 40 publications

Phosphorylation of CMG helicase and Tof1 is required for programmed fork arrest

Phosphorylation of CMG helicase and Tof1 is required for programmed fork arrest

Replication timing is regulated by the number of MCMs loaded at origins

Unexpected roles of a shugoshin protein at subtelomeres

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