Autophagic removal of micronuclei

作者：Rello Varona Santiago; Lissa Delphine; Shen Shensi; Niso Santano Mireia; Senovilla Laura; Marino Guillermo; Vitale Ilio; Jemaa Mohamed; Harper Francis; Pierron Gerard; Castedo Maria; Kroemer Guido^*

来源：Cell Cycle, 2012, 11(1): 170-176.

DOI：10.4161/cc.11.1.18564

• autophagy
• genomic instability
• cell cycle blockage
• micronuclei
• DNA damage foci
• nuclear envelope

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 SP600125), 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. %26quot;Autophagic micronuclei%26quot; (GFP-LC3(+)) were also decorated with p62/SQSTM1, while non-autophagic (GFP-LC3(+)) micronuclei were p62/SQSTM1 negative. In addition, GFP-LC3(+) micronuclei exhibited signs of envelope degradation and gamma H2AX(+) DNA damage foci, yet they 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.

• 出版日期2012-1-1