A P62-dependent Rheostat Dictates Micronuclei Catastrophe and Chromosome Rearrangements

Overview

Journal Science

Specialty Science

Date 2024 Aug 29

PMID 39208097

Authors

Sara Martin

Simone Scorzoni

Sara Cordone

Alice Mazzagatti

Galina V Beznoussenko

Amanda L Gunn

Melody Di Bona

Yonatan Eliezer

Gil Leor

Tal Ben-Yishay

Alessia Loffreda

Valeria Cancila

Maria Chiara Rainone

Marica Rosaria Ippolito

Valentino Martis

Fabio Bedin

Massimiliano Garre

Laura Pontano Vaites

Paolo Vasapolli

Simona Polo

Dario Parazzoli

Claudio Tripodo

Alexander A Mironov

Alessandro Cuomo

Uri Ben-David

Samuel F Bakhoum

Emily M Hatch

Peter Ly

Stefano Santaguida

Affiliations

Soon will be listed here.

Abstract

Chromosomal instability (CIN) generates micronuclei-aberrant extranuclear structures that catalyze the acquisition of complex chromosomal rearrangements present in cancer. Micronuclei are characterized by persistent DNA damage and catastrophic nuclear envelope collapse, which exposes DNA to the cytoplasm. We found that the autophagic receptor p62/SQSTM1 modulates micronuclear stability, influencing chromosome fragmentation and rearrangements. Mechanistically, proximity of micronuclei to mitochondria led to oxidation-driven homo-oligomerization of p62, limiting endosomal sorting complex required for transport (ESCRT)-dependent micronuclear envelope repair by triggering autophagic degradation. We also found that p62 levels correlate with increased chromothripsis across human cancer cell lines and with increased CIN in colorectal tumors. Thus, p62 acts as a regulator of micronuclei and may serve as a prognostic marker for tumors with high CIN.

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