Autophagic removal of micronuclei

Santiago Rello-Varona, Delphine Lissa, Si Shen, Mireia Niso-Santano, Laura Senovilla, Guillermo Mariño, Ilio Vitale, Mohamed Jemaà, Francis Harper, Gérard Pierron, Maria Castedo, Guido Kroemer

Research output: Contribution to journalArticlepeer-review

Abstract

Macroautophagy is known to participate in the quality control and turnover of cytoplasmic organelles, yet there is little evidence that macroautophagy targets nuclei in mammalian cells. Here, we investigated whether autophagy may target micronuclei, which arise as a result of deficient bipolar chromosome segregation in cells exposed to cell cycle perturbations. After removal of several distinct cell cycle blockers (nocodazole, cytochalasin D, hydroxyurea or SP 600125), cells manifested an increase in the frequency of micronuclei (positive for histone H2B-RFP) as well as an increase in autophagic puncta (positive for GFP-LC3) over several days. A small but significant percentage of micronuclei co-localized with GFP-LC3 in autophagy-competent cells and this co-localization was lost after knockdown of ATG5 or ATG7. Electron microscopy analyses confirmed autophagic sequestration of micronuclei. "Autophagic micronuclei"(GFP-LC3 +) were also decorated with p62/SQSTM1, while non-autophagic (GFP-LC3 -) micronuclei where p62/SQSTM1 negative. In addition, GFP-LC3 + micronuclei exhibited signs of envelope degradation and γH2AX + DNA damage foci, yet stained less intensively for chromatin markers, whereas GFP-LC3 - micronuclei were surrounded by an intact envelope and rarely exhibited markers of DNA damage. These results indicate that micronuclei can be subjected to autophagic degradation. Moreover, it can be speculated that removal of micronuclei may contribute to the genome-stabilizing effects of autophagy.

Original languageEnglish
Pages (from-to)170-176
Number of pages7
JournalCell Cycle
Volume11
Issue number1
DOIs
Publication statusPublished - Jan 1 2012

Keywords

  • Autophagy
  • Cell cycle blockage
  • DNA damage foci
  • Genomic instability
  • Micronuclei
  • Nuclear envelope

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Developmental Biology

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