Rad51 suppresses gross chromosomal rearrangement at centromere in Schizosaccharomyces pombe

Nakamura, Ken; Okamoto, Aya; Katou, Yuki; Yadani, Chie; Shitanda, Takeshi; Kaweeteerawat, Chitrada; Takahashi, Tatsuro; Itoh, Takehiko; Shirahige, Katsuhiko; Masukata, Hisao; Nakagawa, Takuro

doi:10.1038/emboj.2008.215

Cited by 61 publications

(118 citation statements)

References 62 publications

Supporting

Mentioning

108

Contrasting

Order By: Relevance

“…However, the rad51 single mutant is sensitive to TBZ (30), making it difficult to compare the phenotypes of the pot1⌬ rqh1-hd double mutant and the pot1⌬ rqh1-hd rad51⌬ triple mutant. Indeed, the pot1⌬ rqh1-hd rad51⌬ triple mutant was sensitive to TBZ, but the TBZ sensitivity of the triple mutant was slightly weaker than that of the double mutant, suggesting that the entangled chromosomal ends in the double mutant affected the TBZ sensitivity (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Fission Yeast Pot1 and RecQ Helicase Are Required for Efficient Chromosome Segregation

Takahashi

Imano

Kibe

et al. 2011

Molecular and Cellular Biology

View full text Add to dashboard Cite

Pot1 is a single-stranded telomere-binding protein that is conserved from fission yeast to mammals. Deletion of Schizosaccharomyces pombe pot1؉ causes immediate telomere loss. S. pombe Rqh1 is a homolog of the human RecQ helicase WRN, which plays essential roles in the maintenance of genomic stability. Here, we demonstrate that a pot1⌬ rqh1-hd (helicase-dead) double mutant maintains telomeres that are dependent on Rad51-mediated homologous recombination. Interestingly, the pot1⌬ rqh1-hd double mutant displays a "cut" (cell untimely torn) phenotype and is sensitive to the antimicrotubule drug thiabendazole (TBZ). Moreover, the chromosome ends of the double mutant do not enter the pulsed-field electrophoresis gel. These results suggest that the entangled chromosome ends in the pot1⌬ rqh1-hd double mutant inhibit chromosome segregation, signifying that Pot1 and Rqh1 are required for efficient chromosome segregation. We also found that POT1 knockdown, WRN-deficient human cells are sensitive to the antimicrotubule drug vinblastine, implying that some of the functions of S. pombe Pot1 and Rqh1 may be conserved in their respective human counterparts POT1 and WRN.

show abstract

Section: Discussionmentioning

confidence: 99%

Fission Yeast Pot1 and RecQ Helicase Are Required for Efficient Chromosome Segregation

Takahashi

Imano

Kibe

et al. 2011

Molecular and Cellular Biology

View full text Add to dashboard Cite

show abstract

“…Rad3 ATR has been previously shown to suppress spontaneous isochromosome formation associated with increased centromeric recombination (42). We therefore tested whether deletion of rad9 + exhibited increased spontaneous centromeric recombination.…”

Section: Resultsmentioning

confidence: 99%

The DNA damage checkpoint pathway promotes extensive resection and nucleotide synthesis to facilitate homologous recombination repair and genome stability in fission yeast

Blaikley

Tinline-Purvis

Kasparek

et al. 2014

Nucleic Acids Research

Self Cite

View full text Add to dashboard Cite

DNA double-strand breaks (DSBs) can cause chromosomal rearrangements and extensive loss of heterozygosity (LOH), hallmarks of cancer cells. Yet, how such events are normally suppressed is unclear. Here we identify roles for the DNA damage checkpoint pathway in facilitating homologous recombination (HR) repair and suppressing extensive LOH and chromosomal rearrangements in response to a DSB. Accordingly, deletion of Rad3ATR, Rad26ATRIP, Crb253BP1 or Cdc25 overexpression leads to reduced HR and increased break-induced chromosome loss and rearrangements. We find the DNA damage checkpoint pathway facilitates HR, in part, by promoting break-induced Cdt2-dependent nucleotide synthesis. We also identify additional roles for Rad17, the 9-1-1 complex and Chk1 activation in facilitating break-induced extensive resection and chromosome loss, thereby suppressing extensive LOH. Loss of Rad17 or the 9-1-1 complex results in a striking increase in break-induced isochromosome formation and very low levels of chromosome loss, suggesting the 9-1-1 complex acts as a nuclease processivity factor to facilitate extensive resection. Further, our data suggest redundant roles for Rad3ATR and Exo1 in facilitating extensive resection. We propose that the DNA damage checkpoint pathway coordinates resection and nucleotide synthesis, thereby promoting efficient HR repair and genome stability.

show abstract

“…6). Aberrant repair via this alternative pathway may underlie the formation of isochromosomes, which account for ϳ50% of spontaneous gross chromosomal rearrangements (GCRs) in fission yeast (50). Rad3 suppresses these GCRs, supporting a model in which they originate from a failure to stabilize stalled replication forks near centromeres.…”

Section: Discussionmentioning

confidence: 99%

γH2A-Binding Protein Brc1 Affects Centromere Function in Fission Yeast

Lee

Rozenzhak

Russell

2013

Molecular and Cellular Biology

View full text Add to dashboard Cite

The coordinated replication and transcription of pericentromeric repeats enable RNA interference (RNAi)-mediated transmission of pericentromeric heterochromatin in fission yeast, which is essential for the proper function of centromeres. Rad3/ATR kinase phosphorylates histone H2A on serine-128/-129 to create ␥H2A in pericentromeric heterochromatin during S phase, which recruits Brc1 through its breast cancer gene 1 protein (BRCA1) C-terminal (BRCT) domains. Brc1 prevents the collapse of stalled replication forks; however, it is unknown whether this activity influences centromere function. Here, we show that Brc1 localizes in pericentromeric heterochromatin during S phase, where it enhances Clr4/Suv39-mediated H3 lysine-9 dimethylation (H3K9me2) and gene silencing. Loss of Brc1 increases sensitivity to the microtubule-destabilizing drug thiabendazole (TBZ) and increases chromosome missegregation in the presence of TBZ. Brc1 retains significant function even when it cannot bind ␥H2A. However, elimination of the serine-121 site on histone H2A, a target of Bub1 spindle assembly checkpoint kinase, sensitizes ␥H2A-deficient and brc1⌬ cells to replication stress and microtubule destabilization. Collective results suggest that Brc1-mediated stabilization of stalled replication forks is necessary for fully efficient transmission of pericentromeric heterochromatin, which is required for accurate chromosome segregation during mitosis. Maintenance of genome integrity during successive cycles of cell division is essential to prevent the accumulation of debilitating genetic alterations and chromosome rearrangements. The responsibility for protecting genome stability falls to highfidelity DNA replication and repair systems acting in conjunction with an accurate chromosome distribution mechanism. DNA damage and mitotic spindle assembly checkpoints regulate these processes and couple their completion to cell cycle progression (1-3).Accurate chromosome segregation depends on the assembly of kinetochores at a single centromere on each chromosome, which serve as the attachment site for microtubules that form the mitotic spindle. In the fission yeast Schizosaccharomyces pombe, the central core domain of each centromere is flanked by large inverted repeats that are themselves composed of shorter repeats. These repeats are the targets of RNA interference (RNAi)-mediated assembly of transcriptionally silent heterochromatin (4-6). A defining feature of this heterochromatin is the dimethylation of histone H3 at lysine 9 (H3k9me2) by the Clr4/Suv39 subunit of Rik1 complex. The heterochromatin protein Swi6/HP1 binds H3k9me2-modified heterochromatin. Failure to maintain pericentromeric heterochromatin impairs centromere function and sister chromatid cohesion near centromeres, leading to increased chromosome loss and sensitivity to the antifungal drug thiabendazole (TBZ), which destabilizes microtubules. Defects in pericentromeric heterochromatin also create a critical requirement for the spindle assembly checkpoint (7). This checkpoint is p...

show abstract

Rad51 suppresses gross chromosomal rearrangement at centromere in Schizosaccharomyces pombe

Cited by 61 publications

References 62 publications

Fission Yeast Pot1 and RecQ Helicase Are Required for Efficient Chromosome Segregation

Fission Yeast Pot1 and RecQ Helicase Are Required for Efficient Chromosome Segregation

The DNA damage checkpoint pathway promotes extensive resection and nucleotide synthesis to facilitate homologous recombination repair and genome stability in fission yeast

γH2A-Binding Protein Brc1 Affects Centromere Function in Fission Yeast

Contact Info

Product

Resources

About