A USP28–53BP1–p53–p21 signaling axis arrests growth after centrosome loss or prolonged mitosis

Abstract

Lambrus et al. show that centrosome loss or a prolonged mitosis activates a USP28–53BP1–p53–p21 signaling axis that prevents the growth of cells with an increased propensity for mitotic errors.

The PIDDosome activates p53 in response to supernumerary centrosomes

“…Whereas DNA damage led to p53-Ser15 phosphorylation, extending the mitotic duration did not (Fig. 3A), consistent with the dispensability of the DDR kinases ATM, Chk1, and Chk2 in this pathway (Lambrus et al 2016). Importantly, p53 stabilized by PIDDosome activation after cytokinesis failure also lacked phosphorylation on Ser15.…”

“…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.…”

“…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.…”

“…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.…”

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

“…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.…”