A5017217632- Microtubule and mitosis dynamics
- DNA Repair Mechanisms
- Cancer, Hypoxia, and Metabolism
- Cardiomyopathy and Myosin Studies
- Cancer-related Molecular Pathways
- Ubiquitin and proteasome pathways
- PARP inhibition in cancer therapy
- Genomics and Chromatin Dynamics
- Photosynthetic Processes and Mechanisms
- CRISPR and Genetic Engineering
- Plant nutrient uptake and metabolism
- Protein Degradation and Inhibitors
- RNA Interference and Gene Delivery
- Cellular transport and secretion
- Virus-based gene therapy research
- Natural product bioactivities and synthesis
- 14-3-3 protein interactions
- Epigenetics and DNA Methylation
- Health Systems, Economic Evaluations, Quality of Life
- Bone and Joint Diseases
- MRI in cancer diagnosis
- CAR-T cell therapy research
- Hemoglobin structure and function
- Chromosomal and Genetic Variations
- Bone health and osteoporosis research
University of Hong Kong
2014-2025
Chinese University of Hong Kong
2023-2024
State Key Laboratory of Synthetic Chemistry
2023
Hong Kong University of Science and Technology
2011-2021
Johns Hopkins University
2021
National University of Singapore
2021
Center for Cancer Research
2012-2015
Kowloon Hospital
2015
Harbin Institute of Technology
2012-2014
University of Helsinki
2014
The role of cyclin B-CDC2 as M phase-promoting factor (MPF) is well established, but the precise functions A remain a crucial outstanding issue. Here we show that down-regulation induces G2 phase arrest through checkpoint-independent inactivation by inhibitory phosphorylation. phenotype rescued expressing resistant to RNA interference. In contrast, B disrupts mitosis without inactivating A-CDK, indicating A-CDK acts upstream B-CDC2. Even when ectopically expressed, cannot replace in driving...
Biochemical studies have indicated that p31(comet) and TRIP13 are critical for inactivating MAD2. To address unequivocally whether required mitotic exit at the cellular level, their genes were ablated either individually or together in human cells. Neither nor absolutely unperturbed mitosis. MAD2 inactivation was only partially impaired p31(comet)-deficient In contrast, TRIP13-deficient cells contained exclusively C-MAD2 conformation. Our results indicate although enhanced TRIP13-mediated...
Huntington's disease (HD) is an autosomal inherited neurological caused by a CAG-repeat expansion in the first exon of huntingtin gene encoding for protein (Htt). In HD, there accumulation intracellular aggregates mutant Htt that negatively influence cellular functions. The contain ubiquitin, and part HD pathophysiology could result from imbalance ubiquitin levels. Deubiquitinating enzymes are important replenishing pool, but less known about their roles brain diseases. We show here...
Abstract NDC80 complex (NDC80C) is composed of four subunits (SPC24, SPC25, NDC80, and NUF2) vital for kinetochore–microtubule (KT–MT) attachment during mitosis. Paradoxically, NDC80C also functions in the activation spindle-assembly checkpoint (SAC). This raises an interesting question regarding how mitosis regulated when levels are compromised. Using a degron-mediated depletion system, we found that acute silencing SPC24 triggered transient mitotic arrest followed by slippage....
The spindle assembly checkpoint (SAC) prevents premature segregation of chromosomes during mitosis. This process requires structural remodeling MAD2 from O-MAD2 to C-MAD2 conformation. After the is satisfied, reverted allow anaphase-promoting complex/cyclosome (APC/C) trigger anaphase. Recently, AAA+-ATPase TRIP13 was shown act in concert with p31comet catalyze C- O-MAD2. Paradoxically, although present TRIP13-deficient cells, SAC cannot be activated. Using a degron-mediated system uncouple...
Abstract Mitotic slippage involves cells exiting mitosis without proper chromosome segregation. Although degradation of cyclin B1 during prolonged mitotic arrest is believed to trigger slippage, its upstream regulation remains obscure. Whether caused by APC/C CDC20 activity that able escape spindle-assembly checkpoint (SAC)-mediated inhibition, or actively promoted a change in SAC an outstanding issue. We found major culprit for reduction MAD2 at the kinetochores, resulting progressive...
Inhibition of cyclin-dependent kinases (CDKs) by Thr14/Tyr15 phosphorylation is critical for normal cell cycle progression and a converging event several checkpoints. In this study, we compared the relative contribution inhibitory cyclin A/B1-CDC2 A/E-CDK2 complexes. We found that plays major role in regulation CDC2 but only minor CDK2 during unperturbed HeLa cells. The importance may reflect their distinct cellular functions. Despite this, expression nonphosphorylation mutants both...
The current paradigm states that exit from mitosis is triggered by the ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C) acting in concert with an activator called CDC20. While this has been well established for a number of systems, evidence critical role CDC20 somatic cells not unequivocal. In study, we reexamined whether mitotic can occur properly after depleted. Using single-cell analysis, found depletion small interfering RNAs (siRNAs) significantly impaired degradation APC/C...
Abstract The G 2 DNA damage checkpoint is one of the most important mechanisms controlling –mitosis transition. kinase Greatwall (MASTL in human) promotes normal transition by inhibiting PP2A via ARPP19 and ENSA. In this study, we demonstrate that MASTL critical for maintaining genome integrity after damage. Although did not affect activation responses subsequent repair, it determined timing entry into mitosis fate recovering cells. Constitutively active promoted dephosphorylation CDK1 Tyr15...
PARP inhibitors have emerged as effective chemotherapeutic agents for BRCA1/BRCA2-deficient cancers. Another DNA damage response protein, ATM, is also increasingly being recognized a target synthetic lethality with inhibitors. As ATM functions in both cell cycle arrest and repair after damage, how cells respond to inhibition of PARP1 yet be defined precisely. We found that loss function, either an ATM-deficient background or treatment (KU-60019 AZD0156), results spontaneous increase...
Limiting genome replication to once per cell cycle is vital for maintaining stability. Inhibition of cyclin-dependent kinase 1 (CDK1) with the specific inhibitor RO3306 sufficient trigger multiple rounds reduplication. We demonstrated that although anaphase-promoting complex/cyclosome (APC/C) remained inactive during initial G(2) arrest, it was activated upon prolonged inhibition CDK1. Using cellular biosensors and live-cell imaging, we provide direct evidence reduplication associated...
The mitotic kinesin KIF11 (also called Eg5) plays critical roles in spindle functions. Although a number of small‐molecule inhibitors are currently clinical development, drug‐resistance could be developed through compensation by another KIF15. Using newly infrared‐based cell system, we discovered that the effectiveness one latest generations inhibitor (SB743921) enhanced with several Aurora A kinase. Evidence including live‐cell imaging and isobologram analysis indicated targeting together...
One of the most intriguing features cell-cycle control is that, although there are multiple cyclin-dependent kinases (CDKs) in higher eukaryotes, a single CDK responsible for both G1-S and G2-M yeasts. By leveraging rapid conditional silencing system human cell lines, we confirm that CDK1 assumes role absence CDK2. Unexpectedly, deficiency does not prevent mitotic entry. Nonetheless, inadequate phosphorylation substrates by noncanonical cyclin B-CDK2 complexes allow progression beyond...
Cyclins and cyclin-dependent kinases (CDKs) orchestrate key events in the cell cycle. However, uniqueness of individual mitotic cyclins has been a long-standing puzzle. By rapidly removing G2 human cells, we found that deficiency B-type attenuates onset uncouples G2–M kinase network from mitosis, resulting sustained activation PLK1 cyclin A–CDK1. This culminates slippage without completing nuclear envelope breakdown. Remarkably, elevating A several-fold above its endogenous level is adequate...
Abstract Hepatocellular carcinoma (HCC) is one of the most prevalent types liver cancer, representing third-leading cause cancer-related mortality worldwide. It typically characterized by an environment high oxidative stress and persistent DNA damage. The damage in HCC triggers initiates ADP-ribosylation signalling pathway, which locates lesion sites for recruitment proteins involved repair. While critical repair, impact disrupting homeostasis on remains poorly understood. To explore...
AbstractSpindle-disrupting agents and CDK inhibitors are important cancer therapeutic agents. Spindle toxins activate the spindle-assembly checkpoint lead to sustained activation of CDK1. Different published results indicate that CDK1 activity is either or dispensable for cytotoxicity associated with spindle disruption. Using live cell imaging various approaches uncoupled mitotic events, we show apoptosis was induced by both prolonged nocodazole treatment as well inhibition after a transient...
Genotoxic stress such as ionizing radiation halts entry into mitosis by activation of the G(2) DNA damage checkpoint. The CHK1 inhibitor 7-hydroxystaurosporine (UCN-01) can bypass checkpoint and induce unscheduled in irradiated cells. Precisely, how cells behave following abrogation remains to be defined. In this study, we tracked fates individual after abrogation, focusing particular on whether they undergo mitotic catastrophe. Surprisingly, while a subset UCN-01-treated were immediately...