53BP1 and USP28 mediate p53 activation and G1 arrest after centrosome loss or extended mitotic duration

Meitinger, Franz; Anzola, John V.; Kaulich, Manuel; Richardson, Amelia; Stender, Joshua D.; Benner, Chris; Glass, Christopher K.; Dowdy, Steven F.; Desai, Arshad; Shiau, Andrew K.; Oegema, Karen

doi:10.1083/jcb.201604081

Cited by 192 publications

(287 citation statements)

References 43 publications

Supporting

Mentioning

261

Contrasting

Order By: Relevance

“…An alternative proposal is that mitosis could simply take more time in the haploids, but in the absence of mis-segregation. In this context, previous studies have shown that prolonged mitosis, even in the absence of segregation problems, leads to an USP28-, p53-, 53BP1-, and P21-dependent G1 arrest in the next interphase (32)(33)(34)(35). However, our findings of no increase in 53BP1 foci in haploid cells, apoptosis rather than G1 arrest in haploid cultures, and no increase in the percentage of haploid HAP1 cells on USP28 or P21 deletion (SI Appendix, Fig.…”

Section: Discussioncontrasting

confidence: 56%

A p53-dependent response limits the viability of mammalian haploid cells

Olbrich

Mayor‐Ruiz

Vega-Sendino

et al. 2017

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

View full text Add to dashboard Cite

The recent development of haploid cell lines has facilitated forward genetic screenings in mammalian cells. These lines include nearhaploid human cell lines isolated from a patient with chronic myelogenous leukemia (KBM7 and HAP1), as well as haploid embryonic stem cells derived from several organisms. In all cases, haploidy was shown to be an unstable state, so that cultures of mammalian haploid cells rapidly become enriched in diploids. Here we show that the observed diploidization is due to a proliferative disadvantage of haploid cells compared with diploid cells. Accordingly, single-cell-sorted haploid mammalian cells maintain the haploid state for prolonged periods, owing to the absence of competing diploids. Although the duration of interphase is similar in haploid and diploid cells, haploid cells spend longer in mitosis, indicative of problems in chromosome segregation. In agreement with this, a substantial proportion of the haploids die at or shortly after the last mitosis through activation of a p53-dependent cytotoxic response. Finally, we show that p53 deletion stabilizes haploidy in human HAP1 cells and haploid mouse embryonic stem cells. We propose that, similar to aneuploidy or tetraploidy, haploidy triggers a p53-dependent response that limits the fitness of mammalian cells.haploidy | embryonic stem cells | p53 | HAP1 | chromosome segregation T he main advantage of yeast as a model organism for genetic studies is the availability of haploid cells, so that the mutation of a single allele can suffice to reveal a phenotype. This approach has been of enormous importance for biomedical research in recent decades, as exemplified by the number of Nobel Prizes awarded to discoveries that used yeast as a model system, including the discovery of autophagy, telomeres, and the cell cycle (1). In any case, there are questions intrinsic to mammalian biology, such as stemness or differentiation, that are difficult to address using yeast as a model, and that could be answered by the availability of mammalian haploid cell lines.

show abstract

Section: Discussioncontrasting

confidence: 56%

A p53-dependent response limits the viability of mammalian haploid cells

Olbrich

Mayor‐Ruiz

Vega-Sendino

et al. 2017

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

View full text Add to dashboard Cite

show abstract

“…Importantly, p53 stabilized by PIDDosome activation after cytokinesis failure also lacked phosphorylation on Ser15. Whereas 53BP1 and USP28 are required for p53 induction upon extended mitotic timing but dispensable for p53-mediated cell cycle arrest upon cytokinesis failure (Fong et al 2016;Lambrus et al 2016;Meitinger et al 2016), we show that the PIDDosome is required for p53 stabilization upon cytokinesis failure but not upon prolonged mitotic timing or DNA damage. Of note, the latter two triggers do not rely on the generation of MDM2 cleavage fragments to activate p53 (Fig.…”

Section: Resultsmentioning

confidence: 88%

“…p53 appears the most relevant effector responding to mitotic defects, inducing cell cycle arrest or cell death following aberrant mitoses (Vitale et al 2011). The triggers of mitotic defects can be very heterogeneous and include (1) DNA damage, occurring as either a consequence of sublethal caspase activation on extended mitosis (Orth et al 2012) or a result of chromosome segregation defects (Janssen et al 2011;Crasta et al 2012); (2) the extension of the mitotic duration itself above a critical threshold (Uetake and Sluder 2010;Fong et al 2016;Lambrus et al 2016;Meitinger et al 2016); (3) chromosome congression/segregation defects (Thompson and Compton 2010;Hinchcliffe et al 2016); and (4) cytokinesis failure or centrosome amplification (Holland et al 2012;Ganem et al 2014). While the first three cues appear clearly distinct from each other, either requiring a definite set of genetic factors for p53 activation or associating with specific markers, it remained elusive whether the presence of extra centrosomes suffices to trigger p53 activation or whether this occurs as a consequence of the resulting CIN.…”

Section: Discussionmentioning

confidence: 99%

“…Perturbations of the centrosome duplication cycle lead to p53 stabilization and p53-dependent cell cycle arrest (Holland et al 2012;Lambrus et al 2015;Wong et al 2015). Of note, while centrosome depletion (or increased mitotic duration) activates p53 via 53BP1 and USP28 (Fong et al 2016;Lambrus et al 2016;Meitinger et al 2016), the molecular machinery activating p53 upon cytokinesis failure or forced generation of extra centrosomes is not understood.…”

mentioning

confidence: 99%

See 1 more Smart Citation

The PIDDosome activates p53 in response to supernumerary centrosomes

et al. 2017

View full text Add to dashboard Cite

Centrosomes, the main microtubule-organizing centers in animal cells, are replicated exactly once during the cell division cycle to form the poles of the mitotic spindle. Supernumerary centrosomes can lead to aberrant cell division and have been causally linked to chromosomal instability and cancer. Here, we report that an increase in the number of mature centrosomes, generated by disrupting cytokinesis or forcing centrosome overduplication, triggers the activation of the PIDDosome multiprotein complex, leading to Caspase-2-mediated MDM2 cleavage, p53 stabilization, and p21-dependent cell cycle arrest. This pathway also restrains the extent of developmentally scheduled polyploidization by regulating p53 levels in hepatocytes during liver organogenesis. Taken together, the PIDDosome acts as a first barrier, engaging p53 to halt the proliferation of cells carrying more than one mature centrosome to maintain genome integrity.

show abstract

“…These authors also reported that mitotic catastrophe-inducing events distinct from cytokinesis abortion, such as prolonged mitosis or DNA damage, initiated the p53 pathway via a mechanism not requiring CASP2 activity, which is in line with previous studies. 11,17,18 Finally, centrosome amplification was identified as the upstream signal triggering CASP2 activation upon cytokinesis abortion. 15 It remains to elucidate how and whether BCL9L and other factors responding to non-diploidy, including large tumor suppressor kinase 2 (LATS2) and the Hyppo pathway, 19 BCL2 proteins, 6 mitogen-activated protein kinase 14 (MAPK14, best known as p38), 9 Cyclin D1 (CCND1) 20 and ubiquitin specific peptidase 28 (USP28), 17,18 may contribute to this CASP2-dependent process.…”

mentioning

confidence: 99%

Caspase 2 in mitotic catastrophe: The terminator of aneuploid and tetraploid cells

Vitale

Manic

Castedo

et al. 2017

Molecular & Cellular Oncology

View full text Add to dashboard Cite

Mitotic catastrophe is an oncosuppressive mechanism that targets cells experiencing defective mitoses via the activation of specific cell cycle checkpoints, regulated cell death pathways and/or cell senescence. This prevents the accumulation of karyotypic aberrations, which otherwise may drive oncogenesis and tumor progression. Here, we summarize experimental evidence confirming the role of caspase 2 (CASP2) as the main executor of mitotic catastrophe, and we discuss the signals that activate CASP2 in the presence of mitotic aberrations. In addition, we summarize the main p53-dependent and -independent effector pathways through which CASP2 limits chromosomal instability and non-diploidy, hence mediating robust oncosuppressive functions.

show abstract

53BP1 and USP28 mediate p53 activation and G1 arrest after centrosome loss or extended mitotic duration

Abstract: Meitinger et al. perform a genome-wide CRISPR/Cas9 screen for centrinone resistance and identify a 53BP1-USP28 module as critical for communicating mitotic challenges to the p53 circuit and TRIM37 as an enforcer of the singularity of centrosome assembly.

Cited by 192 publications

References 43 publications

A p53-dependent response limits the viability of mammalian haploid cells

A p53-dependent response limits the viability of mammalian haploid cells

The PIDDosome activates p53 in response to supernumerary centrosomes

Caspase 2 in mitotic catastrophe: The terminator of aneuploid and tetraploid cells

Contact Info

Product

Resources

About