Bub1: Escapades in a Cellular World

Williams, Grace L.; Roberts, Thomas M.; Gjoerup, Ole

doi:10.4161/cc.6.14.4493

Cited by 38 publications

(39 citation statements)

References 72 publications

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“…Warren et al (39) previously observed that bub1 mutants had about 10-fold higher chromosome loss rates than mad2 strains and suggested that Bub1p (but not Mad2p) had a role in chromosome segregation in the absence of induced spindle damage. A variety of experiments have indicated that Bub1p is important in establishing the correct inner and outer kinetochore structures (40), and cells with low levels or no Bub1p have defective associations between the kinetochore and microtubules, decreased levels of chromosomes that are bioriented at the spindle, and decreased sister chromatid cohesion at the centromere (41). Thus, loss of Bub1p (unlike the loss of Mad2p) leads to defects in the mechanics of chromosome segregation in addition to defects in the SAC, resulting in very high levels of aneuploidy.…”

Section: Discussionmentioning

confidence: 99%

Chromosome rearrangements and aneuploidy in yeast strains lacking both Tel1p and Mec1p reflect deficiencies in two different mechanisms

McCulley

Petes

2010

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

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The human ATM and ATR proteins participate in the DNA damage and DNA replication checkpoint pathways and are critical to maintaining genome stability. The Saccharomyces cerevisiae homologs of ATM and ATR are Tel1p and Mec1p, respectively. Haploid tel1 mec1 strains have very short telomeres and very high rates of chromosomal aberrations. Here, we examine genetic stability in tel1 mec1 diploid cells. In the absence of induced DNA damage, these yeast strains had very high frequencies of aneuploidy (both trisomy and monosomy) in addition to elevated rates of chromosome rearrangements. Although we found the aneuploidy in the tel1 mec1 diploids mimicked that observed in bub1 diploids, the tel1 mec1 diploids had a functional spindle assembly checkpoint. Restoration of wild-type telomere lengths in the tel1 mec1 strain substantially reduced the rate of chromosome rearrangements but had no effect on the frequency of aneuploidy.chromosome nondisjunction | spindle assembly checkpoint | telomeres T wo types of genetic instability are associated with cells derived from solid tumors (1): elevated rates of single-base substitutions/microsatellite alterations and high frequencies of chromosome rearrangements and aneuploidy. The first type of instability is associated with tumors deficient in nucleotide excision repair and DNA mismatch repair. Tumors with elevated rates of chromosome aberrations (deletions, duplications, and translocations) and/or aneuploidy have been termed "chromosome instability" (CIN) tumors (2). Although some CIN tumors have mutations in genes affecting the spindle assembly checkpoint (SAC) (3) or chromatid cohesion (4), the relevant genome-destabilizing mutations have not been identified in most CIN tumors.Many yeast mutants have been identified that have elevated rates of chromosome alterations and/or aneuploidy. One assay designed to detect gross chromosomal rearrangements (GCRs) involves selecting for the deletion of two closely linked markers near the end of chromosome V (5). Mutations that elevate GCRs are found in genes controlling S-phase DNA damage checkpoints (6), DNA replication (7), telomere length regulation (8, 9), and chromatin assembly (10) as well as other pathways. Importantly, strains with mutations in the SAC (which result in elevated levels of chromosome nondisjunction) do not necessarily have elevated rates of GCRs (11), indicating that these two phenotypes are not intrinsically linked.In Saccharomyces cerevisiae, the related kinases Tel1p (orthologous to the mammalian ATM gene) and Mec1p (orthologous to the mammalian ATR gene) have overlapping roles in the DNA damage/S-phase checkpoint and in telomere length regulation (12). In response to DNA damage such as a double-strand break (DSB), Tel1p and Mec1p are recruited to the site of the break, where they initiate a signal transduction cascade that results in phosphorylation and activation of effector proteins, transcription of DNA repair genes, and cell cycle arrest. The tel1 mec1 strains are more sensitive to DNA damaging agents than e...

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Section: Discussionmentioning

confidence: 99%

Chromosome rearrangements and aneuploidy in yeast strains lacking both Tel1p and Mec1p reflect deficiencies in two different mechanisms

McCulley

Petes

2010

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

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“…The most straightforward scenario might be that LT acts as a molecular scaffold to connect Bub1 with its substrate p53. However, as we recently showed, purified recombinant Bub1 phosphorylates only p53 on Ser37 in vitro but not on the other sites (65). Moreover, Bub1 RNA interference could block only Ser37 phosphorylation.…”

Section: Vol 83 2009 Sv40 T-antigen-induced Dna Damage Response Viamentioning

confidence: 99%

Simian Virus 40 Large T Antigen Disrupts Genome Integrity and Activates a DNA Damage Response via Bub1 Binding

Hein

Boichuk

et al. 2009

J Virol

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119

132

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Simian virus 40 (SV40) large T antigen (LT) is a multifunctional protein that is important for viral replication and oncogenic transformation. Previously, infection of monkey or human cells with SV40 was shownto lead to the induction of DNA damage response signaling, which is required for efficient viral replication. However, it was not clear if LT is sufficient to induce the damage response and, if so, what the genetic requirements and functional consequences might be. Here, we show that the expression of LT alone, without a replication origin, can induce key DNA damage response markers including the accumulation of ␥-H2AX and 53BP1 in nuclear foci. Other DNA damage-signaling components downstream of ATM/ATR kinases were induced, including chk1 and chk2. LT also bound the Claspin mediator protein, which normally facilitates the ATR activation of chk1 and monitors cellular replication origins. Stimulation of the damage response by LT depends mainly on binding to Bub1 rather than to the retinoblastoma protein. LT has long been known to stabilize p53 despite functionally inactivating it. We show that the activation of a DNA damage response by LT via Bub1 appears to play a major role in p53 stabilization by promoting the phosphorylation of p53 at Ser15. Accompanying the DNA damage response, LT induces tetraploidy, which is also dependent on Bub1 binding. Taken together, our data suggest that LT, via Bub1 binding, breaches genome integrity mechanisms, leading to DNA damage responses, p53 stabilization, and tetraploidy.Simian virus 40 (SV40) is a small DNA tumor virus, belonging to the polyomavirus family, that induces a productive infection in its natural host, the rhesus macaque, but yields oncogenic transformation in nonpermissive hosts such as rodent cells. The highly multifunctional large T antigen (LT) is the key early protein essential for both driving viral replication as well as inducing cellular transformation. Two other early proteins, small t antigen and 17k T antigen (17k) may perform auxiliary functions during the viral life cycle (39, 69). LT has served as a powerful model system for understanding fundamental cellular processes such as nuclear translocation, transcriptional regulation, eukaryotic DNA replication, immortalization, and malignant transformation (reviewed in references 26 and 37).LT overrides cellular control mechanisms and reprograms the host cell to create a permissive environment for viral replication. The deregulation of cellular proliferation is dependent on LT's interaction with specific host proteins, among which the tumor suppressors p53 and the retinoblastoma protein (pRB) are the best characterized (reviewed in reference 37). Transformation in vitro and tumor induction in vivo frequently depend on LT binding and functionally inactivating these key tumor suppressors (37).

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“…5 Cells with a partial or complete loss of the aforementioned crucial molecules of the mitotic checkpoint manifest insufficient mitotic arrest, chromosome missegregation, abnormal DNA ploidy, senescence, cell death, and cellular transformation. [7][8][9][10] Intriguingly, an overactive mitotic checkpoint also leads to mitotic cell death, chromosome missegregation, and aneuploidy. [11][12][13][14] To illustrate the participation of MTBP in cell cycle regulation and to understand the underlying molecular mechanism, we examined the effects of modulating MTBP expression on cell cycle progression.…”

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confidence: 99%

MTBP plays a crucial role in mitotic progression and chromosome segregation

et al. 2011

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Murine double minute 2 (MDM2) binding protein (MTBP) has been implicated in tumor cell proliferation, but the underlying mechanisms remain unclear. The results of MTBP expression analysis during cell cycle progression demonstrated that MTBP protein was rapidly degraded during mitosis. Immunofluorescence studies revealed that a portion of MTBP was localized at the kinetochores during prometaphase. MTBP overexpression delayed mitotic progression from nuclear envelope breakdown (NEB) to anaphase onset and induced abnormal chromosome segregation such as lagging chromosomes, chromosome bridges, and multipolar chromosome segregation. Conversely, MTBP downmodulation caused an abbreviated metaphase and insufficient mitotic arrest, resulting in abnormal chromosome segregation, aneuploidy, decreased cell proliferation, senescence, and cell death, similar to that of Mad2 (mitotic arrest-deficient 2) downmodulation. Furthermore, MTBP downmodulation inhibited the accumulation of Mad1 and Mad2, but not BubR1 (budding uninhibited by benzimidazoles related 1), on the kinetochores, whereas MTBP overexpression inhibited the release of Mad2 from the metaphase kinetochores. These results may imply that MTBP has an important role in recruiting and/or retaining the Mad1/Mad2 complex at the kinetochores during prometaphase, but its degradation is required for silencing the mitotic checkpoint. Together, this study indicates that MTBP has a crucial role in proper mitotic progression and faithful chromosome segregation, providing new insights into regulation of the mitotic checkpoint. Cell Death and Differentiation (2011) 18, 1208-1219; doi:10.1038/cdd.2010.189; published online 28 January 2011Murine double minute 2 (MDM2) binding protein (MTBP) was originally identified as a protein that interacts with the oncoprotein MDM2, a major negative regulator of the tumor suppressor p53. 1 Overexpression of MTBP was shown to suppress cell proliferation and colony formation of several human cancer cell lines independent of their p53 status. 1 Brady et al. 2 reported that overexpression of MTBP in MCF7 cells resulted in MDM2 stabilization and subsequent p53 degradation. However, our previous findings demonstrated that complete deletion of MTBP in mice resulted in an early embryonic lethal phenotype independent of p53. 3 Furthermore, MTBP heterozygous mice (MTBP þ /À ) were neither tumor prone nor did they show any obvious phenotypes. Nonetheless, Mtbp þ /À p53 þ /À mice showed an increased frequency of metastatic tumors compared with p53 þ /À mice, suggesting the possible involvement of MTBP in tumor progression. 3 Recently, Odvody et al. 4 reported that a reduced MTBP level delayed Myc-induced lymphomagenesis independent of Mdm2 and p53. Thus, a vast majority of the results support the p53-independent functions of MTBP and its involvement in cell proliferation and tumor progression.

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Bub1: Escapades in a Cellular World

Cited by 38 publications

References 72 publications

Chromosome rearrangements and aneuploidy in yeast strains lacking both Tel1p and Mec1p reflect deficiencies in two different mechanisms

Chromosome rearrangements and aneuploidy in yeast strains lacking both Tel1p and Mec1p reflect deficiencies in two different mechanisms

Simian Virus 40 Large T Antigen Disrupts Genome Integrity and Activates a DNA Damage Response via Bub1 Binding

MTBP plays a crucial role in mitotic progression and chromosome segregation

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