A meiotic recombination checkpoint controlled by mitotic checkpoint genes

Nature ◽  
1996 ◽  
Vol 383 (6603) ◽  
pp. 840-843 ◽  
Author(s):  
David Lydall ◽  
Yuri Nikolsky ◽  
Douglas K. Bishop ◽  
Ted Weinert
Keyword(s):  
Meiotic Recombination ◽  
Mitotic Checkpoint ◽  
Recombination Checkpoint ◽  
Checkpoint Genes

scholarly journals Genetic Control of Recombination Partner Preference in Yeast Meiosis: Isolation and Characterization of Mutants Elevated for Meiotic Unequal Sister-Chromatid Recombination

Genetics ◽  
1999 ◽  
Vol 153 (2) ◽  
pp. 621-641 ◽  
Author(s):  
Dawn A Thompson ◽  
Franklin W Stahl
Keyword(s):  
Sister Chromatid ◽  
Meiotic Recombination ◽  
Class Ii ◽  
Class Iii ◽  
Viability Analysis ◽  
Isolation And Characterization ◽  
Recombination Checkpoint ◽  
Recombination Pathway ◽  
Checkpoint Genes ◽  
Sister Chromatid Recombination

AbstractMeiotic exchange occurs preferentially between homologous chromatids, in contrast to mitotic recombination, which occurs primarily between sister chromatids. To identify functions that direct meiotic recombination events to homologues, we screened for mutants exhibiting an increase in meiotic unequal sister-chromatid recombination (SCR). The msc (meiotic sister-chromatid recombination) mutants were quantified in spo13 meiosis with respect to meiotic unequal SCR frequency, disome segregation pattern, sporulation frequency, and spore viability. Analysis of the msc mutants according to these criteria defines three classes. Mutants with a class I phenotype identified new alleles of the meiosis-specific genes RED1 and MEK1, the DNA damage checkpoint genes RAD24 and MEC3, and a previously unknown gene, MSC6. The genes RED1, MEK1, RAD24, RAD17, and MEC1 are required for meiotic prophase arrest induced by a dmc1 mutation, which defines a meiotic recombination checkpoint. Meiotic unequal SCR was also elevated in a rad17 mutant. Our observation that meiotic unequal SCR is elevated in meiotic recombination checkpoint mutants suggests that, in addition to their proposed monitoring function, these checkpoint genes function to direct meiotic recombination events to homologues. The mutants in class II, including a dmc1 mutant, confer a dominant meiotic lethal phenotype in diploid SPO13 meiosis in our strain background, and they identify alleles of UBR1, INP52, BUD3, PET122, ELA1, and MSC1-MSC3. These results suggest that DMC1 functions to bias the repair of meiosis-specific double-strand breaks to homologues. We hypothesize that the genes identified by the class II mutants function in or are regulators of the DMC1-promoted interhomologue recombination pathway. Class III mutants may be elevated for rates of both SCR and homologue exchange.

Saccharomyces cerevisiae Checkpoint Genes MEC1, RAD17 and RAD24 Are Required for Normal Meiotic Recombination Partner Choice

Genetics ◽  
1999 ◽  
Vol 153 (2) ◽  
pp. 607-620 ◽  
Author(s):  
Jeremy M Grushcow ◽  
Teresa M Holzen ◽  
Ken J Park ◽  
Ted Weinert ◽  
Michael Lichten ◽  
...  
Keyword(s):  
Meiotic Recombination ◽  
Mitotic Checkpoint ◽  
Partner Choice ◽  
Wild Type ◽  
Spore Viability ◽  
Checkpoint Signaling ◽  
Ectopic Recombination ◽  
Meiotic Progression ◽  
Checkpoint Genes

Abstract Checkpoint gene function prevents meiotic progression when recombination is blocked by mutations in the recA homologue DMC1. Bypass of dmc1 arrest by mutation of the DNA damage checkpoint genes MEC1, RAD17, or RAD24 results in a dramatic loss of spore viability, suggesting that these genes play an important role in monitoring the progression of recombination. We show here that the role of mitotic checkpoint genes in meiosis is not limited to maintaining arrest in abnormal meioses; mec1-1, rad24, and rad17 single mutants have additional meiotic defects. All three mutants display Zip1 polycomplexes in two- to threefold more nuclei than observed in wild-type controls, suggesting that synapsis may be aberrant. Additionally, all three mutants exhibit elevated levels of ectopic recombination in a novel physical assay. rad17 mutants also alter the fraction of recombination events that are accompanied by an exchange of flanking markers. Crossovers are associated with up to 90% of recombination events for one pair of alleles in rad17, as compared with 65% in wild type. Meiotic progression is not required to allow ectopic recombination in rad17 mutants, as it still occurs at elevated levels in ndt80 mutants that arrest in prophase regardless of checkpoint signaling. These observations support the suggestion that MEC1, RAD17, and RAD24, in addition to their proposed monitoring function, act to promote normal meiotic recombination.

scholarly journals A Role for MMS4 in the Processing of Recombination Intermediates During Meiosis in Saccharomyces cerevisiae

Genetics ◽  
2001 ◽  
Vol 159 (4) ◽  
pp. 1511-1525 ◽  
Author(s):  
Teresa de los Santos ◽  
Josef Loidl ◽  
Brittany Larkin ◽  
Nancy M Hollingsworth
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Meiotic Recombination ◽  
Biochemical Data ◽  
Dna Metabolism ◽  
Spore Viability ◽  
Vegetative Cells ◽  
Recombination Checkpoint

Abstract The MMS4 gene of Saccharomyces cerevisiae was originally identified due to its sensitivity to MMS in vegetative cells. Subsequent studies have confirmed a role for MMS4 in DNA metabolism of vegetative cells. In addition, mms4 diploids were observed to sporulate poorly. This work demonstrates that the mms4 sporulation defect is due to triggering of the meiotic recombination checkpoint. Genetic, physical, and cytological analyses suggest that MMS4 functions after the single end invasion step of meiotic recombination. In spo13 diploids, red1, but not mek1, is epistatic to mms4 for sporulation and spore viability, suggesting that MMS4 may be required only when homologs are capable of undergoing synapsis. MMS4 and MUS81 are in the same epistasis group for spore viability, consistent with biochemical data that show that the two proteins function in a complex. In contrast, MMS4 functions independently of MSH5 in the production of viable spores. We propose that MMS4 is required for the processing of specific recombination intermediates during meiosis.

scholarly journals NDT80 and the Meiotic Recombination Checkpoint Regulate Expression of Middle Sporulation-Specific Genes in Saccharomyces cerevisiae

1998 ◽  
Vol 18 (10) ◽  
pp. 5750-5761 ◽  
Author(s):  
Shelley R. Hepworth ◽  
Helena Friesen ◽  
Jacqueline Segall
Keyword(s):  
Gene Expression ◽  
Saccharomyces Cerevisiae ◽  
Meiotic Recombination ◽  
Active Form ◽  
Specific Gene ◽  
Subsequent Generation ◽  
Genes Encoding ◽  
Recombination Checkpoint ◽  
Sporulation Genes ◽  
Meiosis I

ABSTRACT Distinct classes of sporulation-specific genes are sequentially expressed during the process of spore formation in Saccharomyces cerevisiae. The transition from expression of early meiotic genes to expression of middle sporulation-specific genes occurs at about the time that cells exit from pachytene and form the meiosis I spindle. To identify genes encoding potential regulators of middle sporulation-specific gene expression, we screened for mutants that expressed early meiotic genes but failed to express middle sporulation-specific genes. We identified mutant alleles ofRPD3, SIN3, and NDT80 in this screen. Rpd3p, a histone deacetylase, and Sin3p are global modulators of gene expression. Ndt80p promotes entry into the meiotic divisions. We found that entry into the meiotic divisions was not required for activation of middle sporulation genes; these genes were efficiently expressed in a clb1 clb3 clb4 strain, which fails to enter the meiotic divisions due to reduced Clb-dependent activation of Cdc28p kinase. In contrast, middle sporulation genes were not expressed in a dmc1 strain, which fails to enter the meiotic divisions because a defect in meiotic recombination leads to aRAD17-dependent checkpoint arrest. Expression of middle sporulation genes, as well as entry into the meiotic divisions, was restored to a dmc1 strain by mutation of RAD17. Our studies also revealed that NDT80 was a temporally distinct, pre-middle sporulation gene and that its expression was reduced, but not abolished, on mutation of DMC1,RPD3, SIN3, or NDT80 itself. In summary, our data indicate that Ndt80p is required for expression of middle sporulation genes and that the activity of Ndt80p is controlled by the meiotic recombination checkpoint. Thus, middle genes are expressed only on completion of meiotic recombination and subsequent generation of an active form of Ndt80p.

Methylation of the mitotic checkpoint genes BUB3 and BUBR1 in lung cancer

2004 ◽  
Vol 22 (14_suppl) ◽  
pp. 9558-9558
Author(s):  
N. Alzein ◽  
J. Van Deursen ◽  
J. Molina
Keyword(s):  
Lung Cancer ◽  
Mitotic Checkpoint ◽  
Checkpoint Genes

scholarly journals A tumor suppressor role of the Bub3 spindle checkpoint protein after apoptosis inhibition

2013 ◽  
Vol 201 (3) ◽  
pp. 385-393 ◽  
Author(s):  
Sara Morais da Silva ◽  
Tatiana Moutinho-Santos ◽  
Claudio E. Sunkel
Keyword(s):  
Tumor Suppressor ◽  
Spindle Assembly Checkpoint ◽  
Mitotic Checkpoint ◽  
Proliferative Potential ◽  
Altered Expression ◽  
Apoptosis Inhibition ◽  
Wing Imaginal Discs ◽  
A Minor ◽  
Checkpoint Genes

Most solid tumors contain aneuploid cells, indicating that the mitotic checkpoint is permissive to the proliferation of chromosomally aberrant cells. However, mutated or altered expression of mitotic checkpoint genes accounts for a minor proportion of human tumors. We describe a Drosophila melanogaster tumorigenesis model derived from knocking down spindle assembly checkpoint (SAC) genes and preventing apoptosis in wing imaginal discs. Bub3-deficient tumors that were also deficient in apoptosis displayed neoplastic growth, chromosomal aneuploidy, and high proliferative potential after transplantation into adult flies. Inducing aneuploidy by knocking down CENP-E and preventing apoptosis does not induce tumorigenesis, indicating that aneuploidy is not sufficient for hyperplasia. In this system, the aneuploidy caused by a deficient SAC is not driving tumorigenesis because preventing Bub3 from binding to the kinetochore does not cause hyperproliferation. Our data suggest that Bub3 has a nonkinetochore-dependent function that is consistent with its role as a tumor suppressor.

scholarly journals Mutational Inactivation of Mitotic Checkpoint Genes,hsMAD2andhBUB1, Is Rare in Sporadic Digestive Tract Cancers

1999 ◽  
Vol 90 (8) ◽  
pp. 837-840 ◽  
Author(s):  
Yasuo Imai ◽  
Yasushi Shiratori ◽  
Naoya Kato ◽  
Tohru Inoue ◽  
Masao Omata
Keyword(s):  
Digestive Tract ◽  
Mitotic Checkpoint ◽  
Checkpoint Genes

Mutations of mitotic checkpoint genes in human cancers

Nature ◽  
10.1038/32688 ◽  
1998 ◽  
Vol 392 (6673) ◽  
pp. 300-303 ◽  
Author(s):  
Daniel P. Cahill ◽  
Christoph Lengauer ◽  
Jian Yu ◽  
Gregory J. Riggins ◽  
James K. V. Willson ◽  
...  
Keyword(s):  
Mitotic Checkpoint ◽  
Human Cancers ◽  
Checkpoint Genes

scholarly journals TopBP1 and ATR Colocalization at Meiotic Chromosomes: Role of TopBP1/Cut5 in the Meiotic Recombination Checkpoint

2004 ◽  
Vol 15 (4) ◽  
pp. 1568-1579 ◽  
Author(s):  
David Perera ◽  
Livia Perez-Hidalgo ◽  
Peter B. Moens ◽  
Kaarina Reini ◽  
Nicholas Lakin ◽  
...  
Keyword(s):  
Dna Damage ◽  
Meiotic Recombination ◽  
Early Prophase ◽  
Dna Damage Checkpoint ◽  
Dna Double Strand Breaks ◽  
Direct Role ◽  
Meiotic Chromosomes ◽  
Defective Mutant ◽  
Recombination Checkpoint

Mammalian TopBP1 is a BRCT domain–containing protein whose function in mitotic cells is linked to replication and DNA damage checkpoint. Here, we study its possible role during meiosis in mice. TopBP1 foci are abundant during early prophase I and localize mainly to histone γ-H2AX–positive domains, where DNA double–strand breaks (required to initiate recombination) occur. Strikingly, TopBP1 showed a pattern almost identical to that of ATR, a PI3K-like kinase involved in mitotic DNA damage checkpoint. In the synapsis-defective Fkbp6-/- mouse, TopBP1 heavily stains unsynapsed regions of chromosomes. We also tested whether Schizosaccharomyces pombe Cut5 (the TopBP1 homologue) plays a role in the meiotic recombination checkpoint, like spRad3, the ATR homologue. Indeed, we found that a cut5 mutation suppresses the checkpoint-dependent meiotic delay of a meiotic recombination defective mutant, indicating a direct role of the Cut5 protein in the meiotic checkpoint. Our findings suggest that ATR and TopBP1 monitor meiotic recombination and are required for activation of the meiotic recombination checkpoint.

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