Trends in Cell Biology
ReviewA New Mode of Mitotic Surveillance
Section snippets
Evidence for a Centrosome Sensor
Genome integrity relies on the accurate segregation of chromosomes by the microtubule-based mitotic spindle. As the major microtubule-organizing centers of animal cells, centrosomes guide the formation of the bipolar mitotic spindle. Concordant with this role, centrosome duplication is tightly controlled to ensure the presence of exactly two centrosomes in mitosis (Box 1). When this process errs, the assembly of too many or too few centrosomes leads to abnormal spindle formation that can
Identifying Components of the Centrosome Surveillance Pathway
A centrosome surveillance pathway would be expected to consist of components which, when disrupted, would halt signaling and allow cells to proliferate despite centrosome loss. Recent studies have exploited this logic and used genome-wide CRISPR/Cas9 knockout screening technology [8] to identify components of this pathway 9, 10, 11. The screens were designed to enrich for sgRNAs that allow the continued growth of cells that lose centrosomes after Plk4 inhibition. All of the screens observed
53BP1 and USP28 in Centrosome Surveillance
If they are not acting through their canonical role in the DNA damage response, how, then, do 53BP1 and USP28 function in the centrosome surveillance pathway? Previous work has shown that both p53 and USP28 directly interact with 53BP1 through its BRCT domains 14, 19. The most direct model that can be drawn is that, once triggered by an upstream stimulus, 53BP1 acts as a scaffold to recruit both USP28 and p53 in close proximity, thus allowing USP28 to deubiquitinate p53 and modify its activity.
Centrosome Amplification Arrests the Cell Cycle through a Distinct Pathway
It is important to note that, as with centrosome loss, the production of too many centrosomes has been shown to activate p53-dependent cell cycle arrest [3]. This raises the question of whether the 53BP1–USP28–p53 signaling axis is activated by both centrosome loss and gain. While the idea of a universal centrosome sensor is attractive, knockout of 53BP1 or USP28 did not rescue the cell cycle arrest caused by supernumerary centrosomes [10]. Similarly, while LATS2 signaling was shown to relieve
A Mitotic Clock
A key defect observed in cells lacking centrosomes is that they are slower to assemble spindles and thus spend longer in mitosis 2, 9, 10, 11. An earlier pioneering study demonstrated that prolonged mitosis surpassing a threshold duration (1.5 h in RPE1 cells) is sufficient to trigger p53-dependent cell cycle arrest in daughter cells despite the completion of an otherwise normal division [24]. Analysis of 53BP1−/− and USP28−/− cells that lack centrosomes showed that most divisions surpassed the
The Role of TRIM37 as a Bypass of the Centrosome Surveillance Response
The E3 ligase TRIM37 was also identified in the genome-wide CRISPR screens for increased growth following centrosome loss and is an intriguing mechanistic outlier distinct from the 53BP1–USP28–p53 axis 9, 11. Knockout of TRIM37 prevents p53 stabilization and allows cells to escape arrest following centrosome loss, but unlike 53BP1 and USP28 its depletion does not disrupt mitotic timer function [11]. Studies of TRIM37−/− cells suggest that it relieves centrosome surveillance through a mode of
Concluding Remarks: A New Mode of Mitotic Surveillance
The centrosome surveillance pathway was originally identified based on its requirement in the arrest of cells following centrosome loss. However, more recent work has demonstrated that centrosome surveillance pathway components are also required for the response to prolonged mitosis. We therefore propose that, in the future, a more appropriate descriptive name for the 53BP1–USP28–p53 signaling mechanism will be the ‘mitotic surveillance pathway’. This name respects the fact that current
Acknowledgments
This work was supported by a research grant from the National Institutes of Health (GM 114119) (to A.J.H.) and the NSF GRFP (to B.G.L).
References (33)
- et al.
53BP1: pro choice in DNA repair
Trends Cell Biol.
(2014) A role for the deubiquitinating enzyme USP28 in control of the DNA-damage response
Cell
(2006)The tandem BRCT domain of 53BP1 is not required for its repair function
J. Biol. Chem.
(2006)53BP1 integrates DNA repair and p53-dependent cell fate decisions via distinct mechanisms
Mol. Cell
(2016)Cytokinesis failure triggers Hippo tumor suppressor pathway activation
Cell
(2014)- et al.
Prolonged prometaphase blocks daughter cell proliferation despite normal completion of mitosis
Curr. Biol.
(2010) - et al.
Prolonged prometaphase blocks daughter cell proliferation despite normal completion of mitosis
Curr. Biol.
(2010) Dual regulation of Fbw7 function and oncogenic transformation by Usp28
Cell Rep.
(2014)ATM localization and heterochromatin repair depend on direct interaction of the 53BP1-BRCT2 domain with γH2AX
Cell Rep.
(2015)Reversible centriole depletion with an inhibitor of Polo-like kinase 4
Science
(2015)
p53 protects against genome instability following centriole duplication failure
J. Cell Biol.
The autoregulated instability of Polo-like kinase 4 limits centrosome duplication to once per cell cycle
Genes Dev.
Requirement of a centrosomal activity for cell cycle progression through G1 into S phase
Science
Centrosomes enhance the fidelity of cytokinesis in vertebrates and are required for cell cycle progression
J. Cell Biol.
Acentriolar mitosis activates a p53-dependent apoptosis pathway in the mouse embryo
Proc. Natl Acad. Sci. U. S. A.
Cortical neurogenesis in the absence of centrioles
Nat. Neurosci.
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