Lysosome-mediated processing of chromatin in senescence

Andre Ivanov, Jeff Pawlikowski, Indrani Manoharan, John van Tuyn, David M Nelson, Taranjit Singh Rai, Parisha P Shah, Graeme Hewitt, Viktor I Korolchuk, Joao F Passos, Hong Wu, Shelley L Berger, Peter D Adams

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177 Citations (Scopus)

Abstract

Cellular senescence is a stable proliferation arrest, a potent tumor suppressor mechanism, and a likely contributor to tissue aging. Cellular senescence involves extensive cellular remodeling, including of chromatin structure. Autophagy and lysosomes are important for recycling of cellular constituents and cell remodeling. Here we show that an autophagy/lysosomal pathway processes chromatin in senescent cells. In senescent cells, lamin A/C-negative, but strongly γ-H2AX-positive and H3K27me3-positive, cytoplasmic chromatin fragments (CCFs) budded off nuclei, and this was associated with lamin B1 down-regulation and the loss of nuclear envelope integrity. In the cytoplasm, CCFs were targeted by the autophagy machinery. Senescent cells exhibited markers of lysosomal-mediated proteolytic processing of histones and were progressively depleted of total histone content in a lysosome-dependent manner. In vivo, depletion of histones correlated with nevus maturation, an established histopathologic parameter associated with proliferation arrest and clinical benignancy. We conclude that senescent cells process their chromatin via an autophagy/lysosomal pathway and that this might contribute to stability of senescence and tumor suppression.

Original languageEnglish
Pages (from-to)129-43
Number of pages15
JournalJournal of Cell Biology
Volume202
Issue number1
DOIs
Publication statusPublished - 8 Jul 2013
Externally publishedYes

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Keywords

  • Autophagy
  • Biological Transport
  • Cell Aging
  • Cell Membrane Permeability
  • Cell Nucleus
  • Cells, Cultured
  • Chromatin
  • Chromatin Assembly and Disassembly
  • Cytoplasm
  • Fibroblasts
  • Histones
  • Humans
  • Laminin
  • Lysosomes
  • Nuclear Envelope
  • Proteolysis
  • Time-Lapse Imaging

Cite this

Ivanov, A., Pawlikowski, J., Manoharan, I., van Tuyn, J., Nelson, D. M., Rai, T. S., ... Adams, P. D. (2013). Lysosome-mediated processing of chromatin in senescence. Journal of Cell Biology, 202(1), 129-43. https://doi.org/10.1083/jcb.201212110