Checkpoint control in meiotic prophase: Idiosyncratic demands require unique characteristics

Raina, Vivek B.; Uiterkamp, Maud Schoot; Vader, Gerben

doi:10.1016/bs.ctdb.2022.04.007

Cited by 7 publications

(8 citation statements)

References 250 publications

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“…In response to inappropriate kinetochore‐microtubule attachments during mitosis, the SAC gathers the mitotic checkpoint complex (MCC) to impede the anaphase‐promoting complex/cyclosome, delaying entry into anaphase. The MCC includes CDC20, BUB3, BUBR1 and MAD2, in which BUB1 phosphorylation accelerates MCC assembly 18,20 . BUBR1 phosphorylation on various sites enhances SAC activity in the surveillance of kinetochore–microtubule interactions 21 .…”

Section: Resultsmentioning

confidence: 99%

“…The MCC includes CDC20, BUB3, BUBR1 and MAD2, in which BUB1 phosphorylation accelerates MCC assembly. 18,20 BUBR1 phosphorylation on various sites enhances SAC activity in the surveillance of kinetochore-microtubule interactions. 21 The data demonstrated that 25202 induced a profound band shift of CDC20, BUB1, and BUBR1 (Figure 5), indicating the phosphorylation of these key proteins.…”

Section: Disturbs the Microtubule Organization And Affects Sac Regula...mentioning

confidence: 99%

“…In particular, it needs clear substantiation if HDAC6 inhibition is able to perturb the spindle assembly checkpoint (SAC), a surveillance mechanism in keeping anaphase blockade until all chromosomes precisely reach the metaphase plate, in engaging the anticancer activities. 18 In the current study, we have designed and synthesized several series of quinazolinone-, imidazo [ solution (v/v). The cultures were maintained in a humidified incubator at 37°C in 5% CO 2 /95% air.…”

Section: Introductionmentioning

confidence: 99%

“…However, it needs further elucidation to know whether the impact on microtubule dynamics mediated by selective HDAC6 inhibitors contributes to antineoplastic effects. In particular, it needs clear substantiation if HDAC6 inhibition is able to perturb the spindle assembly checkpoint (SAC), a surveillance mechanism in keeping anaphase blockade until all chromosomes precisely reach the metaphase plate, in engaging the anticancer activities 18 …”

Section: Introductionmentioning

confidence: 99%

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A novel HDAC6 inhibitor interferes microtubule dynamics and spindle assembly checkpoint and sensitizes cisplatin‐induced apoptosis in castration‐resistant prostate cancer

Ye,

Leu,

Yeh

et al. 2024

The Prostate

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BackgroundMetastatic castration‐resistant prostate cancer (CRPC), the most refractory prostate cancer, inevitably progresses and becomes unresponsive to hormone therapy, revealing a pressing unmet need for this disease. Novel agents targeting HDAC6 and microtubule dynamics can be a potential anti‐CRPC strategy.MethodsCell proliferation was examined in CRPC PC‐3 and DU‐145 cells using sulforhodamine B assay and anchorage‐dependent colony formation assay. Flow cytometric analysis of propidium iodide staining was used to determine cell‐cycle progression. Cell‐based tubulin polymerization assay and confocal immunofluorescence microscopic examination determine microtubule assembly/disassembly status. Protein expressions were determined using Western blot analysis.ResultsA total of 82 novel derivatives targeting HDAC6 were designed and synthesized, and Compound 25202 stood out, showing the highest efficacy in blocking HDAC6 (IC50, 3.5 nM in enzyme assay; IC50, 1.0 μM in antiproliferative assay in CRPC cells), superior to tubastatin A (IC50, 5.4 μM in antiproliferative assay). The selectivity and superiority of 25202 were validated by examining the acetylation of both α‐tubulin and histone H3, detecting cell apoptosis and HDACs enzyme activity assessment. Notably, 25202 but not tubastatin A significantly decreased HDAC6 protein expression. 25202 prolonged mitotic arrest through the detection of cyclin B1 upregulation, Cdk1 activation, mitotic phosphoprotein levels, and Bcl‐2 phosphorylation. Compound 25202 did not mimic docetaxel in inducing tubulin polymerization but disrupted microtubule organization. Compound 25202 also increased the phosphorylation of CDC20, BUB1, and BUBR1, indicating the activation of the spindle assembly checkpoint (SAC). Moreover, 25202 profoundly sensitized cisplatin‐induced cell death through impairment of cisplatin‐evoked DNA damage response and DNA repair in both ATR–Chk1 and ATM–Chk2 pathways.ConclusionThe data suggest that 25202 is a novel selective and potent HDAC6 inhibitor. Compound 25202 blocks HDAC6 activity and interferes microtubule dynamics, leading to SAC activation and mitotic arrest prolongation that eventually cause apoptosis of CRPC cells. Furthermore, 25202 sensitizes cisplatin‐induced cell apoptosis through impeding DNA damage repair pathways.

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Section: Resultsmentioning

confidence: 99%

Section: Disturbs the Microtubule Organization And Affects Sac Regula...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A novel HDAC6 inhibitor interferes microtubule dynamics and spindle assembly checkpoint and sensitizes cisplatin‐induced apoptosis in castration‐resistant prostate cancer

Ye,

Leu,

Yeh

et al. 2024

The Prostate

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“…Pch2 is predicted to regulate Hop1 states by pulling apart these interactions (West et al, 2018 ) and thus aiding in the interconversion of Hop1 states. Studies of Hop1 in the meiotic checkpoint, as well as studies of the related Mad2 protein in the mitotic spindle assembly checkpoint, suggest that these different conformational states have different functions (Raina and Vader, 2020 ; Raina et al, 2023 ).…”

Section: Discussionmentioning

confidence: 99%

Chromatin binding by HORMAD proteins regulates meiotic recombination initiation

Milano,

Ur,

et al. 2024

EMBO J

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The meiotic chromosome axis coordinates chromosome organization and interhomolog recombination in meiotic prophase and is essential for fertility. In S. cerevisiae, the HORMAD protein Hop1 mediates the enrichment of axis proteins at nucleosome-rich islands through a central chromatin-binding region (CBR). Here, we use cryoelectron microscopy to show that the Hop1 CBR directly recognizes bent nucleosomal DNA through a composite interface in its PHD and winged helix–turn–helix domains. Targeted disruption of the Hop1 CBR-nucleosome interface causes a localized reduction of axis protein binding and meiotic DNA double-strand breaks (DSBs) in axis islands and leads to defects in chromosome synapsis. Synthetic effects with mutants of the Hop1 regulator Pch2 suggest that nucleosome binding delays a conformational switch in Hop1 from a DSB-promoting, Pch2-inaccessible state to a DSB-inactive, Pch2-accessible state to regulate the extent of meiotic DSB formation. Phylogenetic analyses of meiotic HORMADs reveal an ancient origin of the CBR, suggesting that the mechanisms we uncover are broadly conserved.

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Aurora B kinase erases monopolar microtubule-kinetochore arrays at the meiosis I-II transition

Villa-Consuegra,

Tallada,

Jimenez

2023

iScience

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Checkpoint control in meiotic prophase: Idiosyncratic demands require unique characteristics

Cited by 7 publications

References 250 publications

A novel HDAC6 inhibitor interferes microtubule dynamics and spindle assembly checkpoint and sensitizes cisplatin‐induced apoptosis in castration‐resistant prostate cancer

A novel HDAC6 inhibitor interferes microtubule dynamics and spindle assembly checkpoint and sensitizes cisplatin‐induced apoptosis in castration‐resistant prostate cancer

Chromatin binding by HORMAD proteins regulates meiotic recombination initiation

Aurora B kinase erases monopolar microtubule-kinetochore arrays at the meiosis I-II transition

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