Elimination of Replication Block Protein Fob1 Extends the Life Span of Yeast Mother Cells

Defossez, Pierre‐Antoine; Prusty, Reeta; Kaeberlein, Matt; Lin, Su; Ferrigno, Paul Ko; Silver, Pamela A.; Keil, Ralph L.; Guarente, Leonard

doi:10.1016/s1097-2765(00)80472-4

Cited by 384 publications

(412 citation statements)

References 48 publications

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“…In contrast, FOB1 deletion cells display the opposite aging phenotype. The absence of FOB1 reduces recombination and the formation of ERCs, extends average life span, and as expected, suppresses premature aging in cells lacking SIR2 (Defossez et al 1999).…”

supporting

confidence: 74%

“…Fob1-GFP has been shown to localize to the nucleolus (Defossez et al 1999), but it is not known if Fob1 actually associates with rDNA. To determine if Fob1 is associated with the NTS1 region, we mapped the association of Fob1 with rDNA by ChIP, using a strain in which the endogenous FOB1 gene was modified to produce a protein with a C-terminal TAP tag (Fob1-TAP; Fig.…”

Section: Fob1 Colocalizes With Net1 and Sir2 To The Rfb Region Of Nts1mentioning

confidence: 99%

“…Cold Spring Harbor Laboratory Press on May 12, 2018 -Published by genesdev.cshlp.org Downloaded from tion and yeast life span (Gottlieb and Esposito 1989;Kobayashi and Horiuchi 1996;Defossez et al 1999;Kaeberlein et al 1999;Johzuka and Horiuchi 2002). Fob1, a positive regulator of rDNA recombination, recruits its own inhibitor, Sir2, to rDNA.…”

Section: Genes and Development 2171mentioning

confidence: 99%

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Association of the RENT complex with nontranscribed and coding regions of rDNA and a regional requirement for the replication fork block protein Fob1 in rDNA silencing

Huang¹,

Moazed²

2003

Genes Dev.

212

322

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Silencing within the yeast rDNA repeats inhibits hyperrecombination, represses transcription from foreign promoters, and extends replicative life span. rDNA silencing is mediated by a Sir2-containing complex called RENT (regulator of nucleolar silencing and telophase exit). We show that the Net1 (also called Cfi1) and Sir2 subunits of RENT localize primarily to two distinct regions within rDNA: in one of the nontranscribed spacers (NTS1) and around the Pol I promoter, extending into the 35S rRNA coding region. Binding to NTS1 overlaps the recombination hotspot and replication fork barrier elements, which have been shown previously to require the Fob1 protein for their activities. In cells lacking Fob1, silencing and the association of RENT subunits are abolished specifically at NTS1, while silencing and association at the Pol I promoter region are unaffected or increased. We find that Net1 and Sir2 are physically associated with Fob1 and subunits of RNA polymerase I. Together with the localization data, these results suggest the existence of two distinct modes for the recruitment of the RENT complex to rDNA and reveal a role for Fob1 in rDNA silencing and in the recruitment of the RENT complex. Furthermore, the Fob1-dependent associations of Net1 and Sir2 with the recombination hotspot region strongly suggest that Sir2 acts directly at this region to carry out its inhibitory effect on rDNA recombination and accelerated aging.[Keywords: Gene silencing; chromatin; Sir2; recombination; Fob1; rDNA] Supplemental material is available at http://www.genesdev.org.

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supporting

confidence: 74%

Section: Fob1 Colocalizes With Net1 and Sir2 To The Rfb Region Of Nts1mentioning

confidence: 99%

Section: Genes and Development 2171mentioning

confidence: 99%

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Association of the RENT complex with nontranscribed and coding regions of rDNA and a regional requirement for the replication fork block protein Fob1 in rDNA silencing

Huang¹,

Moazed²

2003

Genes Dev.

212

322

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“…In S. cerevisiae, a central component of rDNA maintenance is the Fob1 protein that plays an important role in the control of the expansion and contraction of the rDNA copy number (Kobayashi et al, 1992(Kobayashi et al, , 1998Kobayashi and Horiuchi, 1996;Defossez et al, 1999). Fob1 binds at the polar Replication Fork Barrier (RFB) where it blocks RFs from moving into an adjacent rDNA repeat in a direction opposite to that of rDNA transcription.…”

Section: Slx1-slx4 Endonucleasementioning

confidence: 99%

“…The resulting ds end would be processed into a 3Ј-ss end by 5Ј to 3Ј resection and an active RF reconstructed after the free 3Ј end reinvades the intact chromatid. Downstream or upstream strand invasion of the sister chromatid leads to contraction or expansion, respectively, of the rDNA repeats (Kobayashi et al, 1998;Defossez et al, 1999;Johzuka and Horiuchi, 2002), whereas invasion within the same chromatid results in formation of extrachromosomal DNA circles. Interestingly, the absence of Sgs1 results in an accumulation of extrachromosomal DNA circles in a Fob1-independent manner, suggesting that Sgs1 is also required for the nonrecombinogenic rescue of RFs that have stalled within the rDNA loci but not at the RFB (Sinclair and Guarente, 1997;Park et al, 1999).…”

Section: Slx1-slx4 Endonucleasementioning

confidence: 99%

Slx1-Slx4 Are Subunits of a Structure-specific Endonuclease That Maintains Ribosomal DNA in Fission Yeast

Coulon

Gaillard

Chahwan

et al. 2004

MBoC

109

173

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In most eukaryotes, genes encoding ribosomal RNAs (rDNA) are clustered in long tandem head-to-tail repeats. Studies of Saccharomyces cerevisiae have indicated that rDNA copy number is maintained through recombination events associated with site-specific blockage of replication forks (RFs). Here, we describe two Schizosaccharomyces pombe proteins, homologs of S. cerevisiae Slx1 and Slx4, as subunits of a novel type of endonuclease that maintains rDNA copy number. The Slx1-Slx4 -dependent endonuclease introduces single-strand cuts in duplex DNA on the 3 side of junctions with single-strand DNA. Deletion of Slx1 or Rqh1 RecQ-like DNA helicase provokes rDNA contraction, whereas simultaneous elimination of Slx1-Slx4 endonuclease and Rqh1 is lethal. Slx1 associates with chromatin at two foci characteristic of the two rDNA repeat loci in S. pombe. We propose a model in which the Slx1-Slx4 complex is involved in the control of the expansion and contraction of the rDNA loci by initiating recombination events at stalled RFs. INTRODUCTIONAccurate duplication of a eukaryotic genome depends on highly proficient DNA replication machinery acting in conjunction with DNA repair and checkpoint signaling pathways Osborn et al., 2002). Repair and checkpoint systems are vital because replisomes stall when they encounter DNA damage, protein complexes, or torsional stress. Arrested replication forks (RFs) are prone to rearrangement or collapse. Studies of bacteria have shown that stalled forks can be rescued through either recombinogenic or nonrecombinogenic pathways (Seigneur et al., 1998;Cox et al., 2000;Seigneur et al., 2000;Cox, 2001;McGlynn and Lloyd, 2002).Recent studies have indicated that eukaryotes rescue stalled forks by mechanisms similar to those proposed to act in prokaryotes (Doe et al., 2000;Cox, 2001). A conserved family of eukaryotic DNA helicases related to Escherichia coli RecQ helicase seems to play a central role in the rescue of stalled forks through a nonrecombinogenic mechanism (Doe et al., 2000;Cox, 2001;Hickson et al., 2001). The crucial role of these RecQ-related helicases in maintenance of genome integrity is underscored by the pleiotropic phenotypes of the human Bloom, Werner, and Rothmund-Thomson syndromes associated with defects in BLM, WRN, and RecQ4 proteins, respectively. These hereditary disorders are characterized by high genomic instability, cancer predisposition and, in the case of Werner syndrome, also premature aging (Shen and Loeb, 2000). In budding yeast, Saccharomyces cerevisiae and fission yeast Schizosaccharomyces pombe, mutations in the genes encoding the RecQ-related helicases Sgs1 and Rqh1, respectively, are associated with hyper-recombination phenotypes. The sgs1 phenotype is characterized by an increase in intra-and interchromosomal recombination, especially at the tandem repeated ribosomal DNA (rDNA) loci (Watt et al., 1995;Sinclair and Guarente, 1997), whereas rqh1 mutants are unable to segregate their chromosomes properly under conditions that stall replication (Stewart et al., 1997...

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Mitotic recombination in yeast: elements controlling its incidence

Aguilera

Chávez

Malagón

2000

Yeast

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Elimination of Replication Block Protein Fob1 Extends the Life Span of Yeast Mother Cells

Cited by 384 publications

References 48 publications

Association of the RENT complex with nontranscribed and coding regions of rDNA and a regional requirement for the replication fork block protein Fob1 in rDNA silencing

Association of the RENT complex with nontranscribed and coding regions of rDNA and a regional requirement for the replication fork block protein Fob1 in rDNA silencing

Slx1-Slx4 Are Subunits of a Structure-specific Endonuclease That Maintains Ribosomal DNA in Fission Yeast

Mitotic recombination in yeast: elements controlling its incidence

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