Centrosomal p53 has been described for three decades but its role is still unclear. We previously reported that, in proliferating human cells, p53 transiently moves to centrosomes at each mitosis. Such p53 mitotic centrosome localization (p53-MCL) occurs independently from DNA damage but requires ATM-mediated p53Ser15 phosphorylation (p53Ser15P) on discrete cytoplasmic p53 foci that, through MT dynamics, move to centrosomes during the mitotic spindle formation. Here, we show that inhibition of p53-MCL, obtained by p53 depletion or selective impairment of p53 centrosomal localization, induces centrosome fragmentation in human nontransformed cells. In contrast, tumor cells or mouse cells tolerate p53 depletion, as expected, and p53-MCL inhibition. Such tumor- and species-specific behavior of centrosomal p53 resembles that of the recently identified sensor of centrosome-loss, whose activation triggers the mitotic surveillance pathway in human nontransformed cells but not in tumor cells or mouse cells. The mitotic surveillance pathway prevents the growth of human cells with increased chance of making mitotic errors and accumulating numeral chromosome defects. Thus, we evaluated whether p53-MCL could work as a centrosome-loss sensor and contribute to the activation of the mitotic surveillance pathway. We provide evidence that centrosome-loss triggered by PLK4 inhibition makes p53 orphan of its mitotic dock and promotes accumulation of discrete p53Ser15P foci. These p53 foci are required for the recruitment of 53BP1, a key effector of the mitotic surveillance pathway. Consistently, cells from patients with constitutive impairment of p53-MCL, such as ATM- and PCNT-mutant carriers, accumulate numeral chromosome defects. These findings indicate that, in nontransformed human cells, centrosomal p53 contributes to safeguard genome integrity by working as sensor for the mitotic surveillance pathway.

p53 mitotic centrosome localization preserves centrosome integrity and works as sensor for the mitotic surveillance pathway / Contadini, C.; Monteonofrio, L.; Virdia, I.; Prodosmo, A.; Valente, D.; Chessa, L.; Musio, A.; Fava, Luca; Rinaldo, C.; Di Rocco, G.; Soddu, S.. - In: CELL DEATH & DISEASE. - ISSN 2041-4889. - STAMPA. - 10:11(2019), pp. 85001-85016. [10.1038/s41419-019-2076-1]

p53 mitotic centrosome localization preserves centrosome integrity and works as sensor for the mitotic surveillance pathway

Fava Luca;
2019-01-01

Abstract

Centrosomal p53 has been described for three decades but its role is still unclear. We previously reported that, in proliferating human cells, p53 transiently moves to centrosomes at each mitosis. Such p53 mitotic centrosome localization (p53-MCL) occurs independently from DNA damage but requires ATM-mediated p53Ser15 phosphorylation (p53Ser15P) on discrete cytoplasmic p53 foci that, through MT dynamics, move to centrosomes during the mitotic spindle formation. Here, we show that inhibition of p53-MCL, obtained by p53 depletion or selective impairment of p53 centrosomal localization, induces centrosome fragmentation in human nontransformed cells. In contrast, tumor cells or mouse cells tolerate p53 depletion, as expected, and p53-MCL inhibition. Such tumor- and species-specific behavior of centrosomal p53 resembles that of the recently identified sensor of centrosome-loss, whose activation triggers the mitotic surveillance pathway in human nontransformed cells but not in tumor cells or mouse cells. The mitotic surveillance pathway prevents the growth of human cells with increased chance of making mitotic errors and accumulating numeral chromosome defects. Thus, we evaluated whether p53-MCL could work as a centrosome-loss sensor and contribute to the activation of the mitotic surveillance pathway. We provide evidence that centrosome-loss triggered by PLK4 inhibition makes p53 orphan of its mitotic dock and promotes accumulation of discrete p53Ser15P foci. These p53 foci are required for the recruitment of 53BP1, a key effector of the mitotic surveillance pathway. Consistently, cells from patients with constitutive impairment of p53-MCL, such as ATM- and PCNT-mutant carriers, accumulate numeral chromosome defects. These findings indicate that, in nontransformed human cells, centrosomal p53 contributes to safeguard genome integrity by working as sensor for the mitotic surveillance pathway.
2019
11
Contadini, C.; Monteonofrio, L.; Virdia, I.; Prodosmo, A.; Valente, D.; Chessa, L.; Musio, A.; Fava, Luca; Rinaldo, C.; Di Rocco, G.; Soddu, S.
p53 mitotic centrosome localization preserves centrosome integrity and works as sensor for the mitotic surveillance pathway / Contadini, C.; Monteonofrio, L.; Virdia, I.; Prodosmo, A.; Valente, D.; Chessa, L.; Musio, A.; Fava, Luca; Rinaldo, C.; Di Rocco, G.; Soddu, S.. - In: CELL DEATH & DISEASE. - ISSN 2041-4889. - STAMPA. - 10:11(2019), pp. 85001-85016. [10.1038/s41419-019-2076-1]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11572/249430
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