A p62-dependent rheostat dictates micronuclei catastrophe and chromosome rearrangements

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 Garrè; 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

doi:10.1126/science.adj7446

A p62-dependent rheostat dictates micronuclei catastrophe and chromosome rearrangements

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 Garrè, Laura Pontano Vaites, Paolo Vasapolli, Simona PoloDario Parazzoli, Claudio Tripodo, Alexander A. Mironov, Alessandro Cuomo, Uri Ben-David, Samuel F. Bakhoum, Emily M. Hatch, Peter Ly, Stefano Santaguida

Human Molecular Genetics Biochemistry

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

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.

Original language	English
Pages (from-to)	eadj7446
Journal	Science
Volume	385
Issue number	6712
DOIs	https://doi.org/10.1126/science.adj7446
State	Published - 30 Aug 2024

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Martin, S., Scorzoni, S., Cordone, S., Mazzagatti, A., Beznoussenko, G. V., Gunn, A. L., Di Bona, M., Eliezer, Y., Leor, G., Ben-Yishay, T., Loffreda, A., Cancila, V., Rainone, M. C., Ippolito, M. R., Martis, V., Bedin, F., Garrè, M., Vaites, L. P., Vasapolli, P., ... Santaguida, S. (2024). A p62-dependent rheostat dictates micronuclei catastrophe and chromosome rearrangements. Science, 385(6712), eadj7446. https://doi.org/10.1126/science.adj7446

@article{dc8f7d2258b04b82b4b934b061b0b971,

title = "A p62-dependent rheostat dictates micronuclei catastrophe and chromosome rearrangements",

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.",

author = "Sara Martin and Simone Scorzoni and Sara Cordone and Alice Mazzagatti and Beznoussenko, {Galina V.} and Gunn, {Amanda L.} and {Di Bona}, Melody and Yonatan Eliezer and Gil Leor and Tal Ben-Yishay and Alessia Loffreda and Valeria Cancila and Rainone, {Maria Chiara} and Ippolito, {Marica Rosaria} and Valentino Martis and Fabio Bedin and Massimiliano Garr{\`e} and Vaites, {Laura Pontano} and Paolo Vasapolli and Simona Polo and Dario Parazzoli and Claudio Tripodo and Mironov, {Alexander A.} and Alessandro Cuomo and Uri Ben-David and Bakhoum, {Samuel F.} and Hatch, {Emily M.} and Peter Ly and Stefano Santaguida",

year = "2024",

month = aug,

day = "30",

doi = "10.1126/science.adj7446",

language = "אנגלית",

volume = "385",

pages = "eadj7446",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

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Martin, S, Scorzoni, S, Cordone, S, Mazzagatti, A, Beznoussenko, GV, Gunn, AL, Di Bona, M, Eliezer, Y, Leor, G, Ben-Yishay, T, Loffreda, A, Cancila, V, Rainone, MC, Ippolito, MR, Martis, V, Bedin, F, Garrè, M, Vaites, LP, Vasapolli, P, Polo, S, Parazzoli, D, Tripodo, C, Mironov, AA, Cuomo, A, Ben-David, U, Bakhoum, SF, Hatch, EM, Ly, P & Santaguida, S 2024, 'A p62-dependent rheostat dictates micronuclei catastrophe and chromosome rearrangements', Science, vol. 385, no. 6712, pp. eadj7446. https://doi.org/10.1126/science.adj7446

TY - JOUR

T1 - A p62-dependent rheostat dictates micronuclei catastrophe and chromosome rearrangements

AU - Martin, Sara

AU - Scorzoni, Simone

AU - Cordone, Sara

AU - Mazzagatti, Alice

AU - Beznoussenko, Galina V.

AU - Gunn, Amanda L.

AU - Di Bona, Melody

AU - Eliezer, Yonatan

AU - Leor, Gil

AU - Ben-Yishay, Tal

AU - Loffreda, Alessia

AU - Cancila, Valeria

AU - Rainone, Maria Chiara

AU - Ippolito, Marica Rosaria

AU - Martis, Valentino

AU - Bedin, Fabio

AU - Garrè, Massimiliano

AU - Vaites, Laura Pontano

AU - Vasapolli, Paolo

AU - Polo, Simona

AU - Parazzoli, Dario

AU - Tripodo, Claudio

AU - Mironov, Alexander A.

AU - Cuomo, Alessandro

AU - Ben-David, Uri

AU - Bakhoum, Samuel F.

AU - Hatch, Emily M.

AU - Ly, Peter

AU - Santaguida, Stefano

PY - 2024/8/30

Y1 - 2024/8/30

N2 - 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.

AB - 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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U2 - 10.1126/science.adj7446

DO - 10.1126/science.adj7446

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C2 - 39208097

AN - SCOPUS:85203116526

SN - 0036-8075

VL - 385

SP - eadj7446

JO - Science

JF - Science

IS - 6712

ER -

A p62-dependent rheostat dictates micronuclei catastrophe and chromosome rearrangements

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