skip to primary navigationskip to content

25.11.16 Two Cdc20-binding sequences play key role in preventing incorrect chromatid separation

last modified Dec 15, 2016 09:31 AM
Di Fiore et al. from the Pines lab identify conserved sequence motifs that mediate inhibition of active APC/C
25.11.16 Two Cdc20-binding sequences play key role in preventing incorrect chromatid separation

Graphical abstract from the paper in Molecular Celll

The Mitotic Checkpoint Complex Requires an Evolutionary Conserved Cassette to Bind and Inhibit Active APC/C

Di Fiore B, Wurzenberger C, Davey NE & Pines J. (2016) Mol Cell. Nov 25. DOI: 10.1016/j.molcel.2016.11.006. [Epub ahead of print]


The authors are investigating the fine details of cell division (mitosis) in the stages leading up to anaphase, when replicated sister chromatids are pulled apart to opposite ends of the cell in order to give the correct complement of chromosomes to both of the daughter cells.

Working with a colleague in Dublin, they show that two newly identified ABBA motifs (sequences) in protein BubR1, part of the Mitotic Checkpoint Complex (MCC), are crucial because they mediate the binding of the Mitotic Checkpoint Complex (MCC) to inhibit the Anaphase Promoting Complex/ Cyclostome (APC/C). The inhibition occurs via the binding of Cdc20 to both ABBA motifs, where one Cdc20 is part of the MCC and the other part of the APC/C. These results help explain how the MCC distinguishes and preferentially binds active APC/C, which will happen when there is a need to inhibit the cell moving to anaphase.

The ABBA motifs are part of a longer sequence that is highly conserved throughout evolution, another pointer to the crucial role they play in regulating cell division.

The authors suggest that the ABBA motif may provide a target for small molecule inhibitors with the effect of disrupting mitosis, for example in rapidly-dividing cancer cells.


Abstract from the paper

The Spindle Assembly Checkpoint (SAC) ensures genomic stability by preventing sister chromatid separation until all chromosomes are attached to the spindle. It catalyzes the production of the Mitotic Checkpoint Complex (MCC), which inhibits Cdc20 to inactivate the Anaphase Promoting Complex/Cyclosome (APC/C). Here we show that two Cdc20-binding motifs in BubR1 of the recently identified ABBA motif class are crucial for the MCC to recognize active APC/C-Cdc20. Mutating these motifs eliminates MCC binding to the APC/C, thereby abolishing the SAC and preventing cells from arresting in response to microtubule poisons. These ABBA motifs flank a KEN box to form a cassette that is highly conserved through evolution, both in the arrangement and spacing of the ABBA-KEN-ABBA motifs, and association with the amino-terminal KEN box required to form the MCC. We propose that the ABBA-KEN-ABBA cassette holds the MCC onto the APC/C by binding the two Cdc20 molecules in the MCC-APC/C complex.


Read more about research in the Pines lab.

Studying development to understand disease

The Gurdon Institute is funded by Wellcome and Cancer Research UK to study the biology of development, and how normal growth and maintenance go wrong in cancer and other diseases.

combinedLogo x3 trans2018


Share this

Extracellular Forms of Aβ and Tau from iPSC Models of Alzheimer's Disease Disrupt Synaptic Plasticity

Combinational Treatment of Trichostatin A and Vitamin C Improves the Efficiency of Cloning Mice by Somatic Cell Nuclear Transfer

Predominant Asymmetrical Stem Cell Fate Outcome Limits the Rate of Niche Succession in Human Colonic Crypts

G9a regulates temporal preimplantation developmental program and lineage segregation in blastocyst

Validating the concept of mutational signatures with isogenic cell models

A PAX5-OCT4-PRDM1 developmental switch specifies human primordial germ cells

Targeting NAT10 enhances healthspan and lifespan in a mouse model of human accelerated aging syndrome

An alternative mode of epithelial polarity in the Drosophila midgut

Detection of functional protein domains by unbiased genome-wide forward genetic screening

Fank1 and Jazf1 promote multiciliated cell differentiation in the mouse airway epithelium

Genome organization at different scales: nature, formation and function

Mouse Model of Alagille Syndrome and Mechanisms of Jagged1 Missense Mutations

Cell cycle heterogeneity directs the timing of neural stem cell activation from quiescence

Functional Studies of Missense TREM2 Mutations in Human Stem Cell-Derived Microglia

Extracellular Monomeric and Aggregated Tau Efficiently Enter Human Neurons through Overlapping but Distinct Pathways

Systematic Analysis of the DNA Damage Response Network in Telomere Defective Budding Yeast

Genomic positional conservation identifies topological anchor point RNAs linked to developmental loci








Link to full list on PubMed