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A p62-dependent rheostat dictates micronuclei catastrophe and chromosome rearrangements

Sara Martin1, Simone Scorzoni1, Sara Cordone1

  • 1Department of Experimental Oncology at IEO, European Institute of Oncology IRCCS, Milan, Italy.

Science (New York, N.Y.)
|August 29, 2024
PubMed

Insights

The autophagic receptor p62 regulates micronuclear stability, impacting chromosome damage in cancer. Elevated p62 levels are linked to increased chromosomal instability (CIN) and may predict tumor prognosis.

Area of Science:

  • Cell Biology
  • Genetics
  • Cancer Research

Background:

  • Chromosomal instability (CIN) drives cancer development through complex chromosomal rearrangements.
  • Micronuclei, resulting from CIN, contain damaged DNA and undergo nuclear envelope collapse, exposing DNA to the cytoplasm.
  • The mechanisms regulating micronuclear stability and its role in cancer progression are not fully understood.

Purpose of the Study:

  • To investigate the role of the autophagic receptor p62/SQSTM1 in modulating micronuclear stability.
  • To elucidate the molecular mechanisms by which p62 influences chromosome fragmentation and rearrangements within micronuclei.
  • To assess the correlation between p62 levels, chromothripsis, and CIN in human cancer.

Main Methods:

  • Assessed the impact of p62/SQSTM1 on micronuclear stability and chromosome integrity.
  • Investigated the mechanism involving p62 homo-oligomerization, mitochondrial proximity, and oxidation.
  • Examined the role of the endosomal sorting complex required for transport (ESCRT) pathway in micronuclear envelope repair.
  • Analyzed p62 expression levels in human cancer cell lines and colorectal tumors in relation to chromothripsis and CIN.

Main Results:

  • p62/SQSTM1 was identified as a key modulator of micronuclear stability.
  • Proximity to mitochondria induced oxidation-dependent p62 homo-oligomerization, hindering ESCRT-mediated repair and promoting autophagic degradation.
  • p62 levels positively correlated with increased chromothripsis in cancer cell lines and elevated CIN in colorectal tumors.
  • p62 acts as a regulator of micronuclear integrity and DNA damage.

Conclusions:

  • p62/SQSTM1 plays a critical role in regulating micronuclear stability and influencing chromosomal rearrangements.
  • The findings reveal a novel mechanism linking p62, mitochondria, and DNA damage within micronuclei.
  • p62 may serve as a prognostic biomarker for cancers characterized by high chromosomal instability.

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