Lysosome-mediated processing of chromatin in senescence.

Ivanov A, Pawlikowski J, Manoharan I, van Tuyn J, Nelson DM, Rai TS, Shah PP, Hewitt G, Korolchuk VI, Passos JF, Wu H, Berger SL, Adams PD
J Cell Biol. 2013 202 (1): 129-43

PMID: 23816621 · PMCID: PMC3704985 · DOI:10.1083/jcb.201212110

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.

MeSH Terms (17)

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

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