TY - JOUR
T1 - Lysosome-mediated processing of chromatin in senescence
AU - Adams, Peter D.
AU - Ivanov, Andre
AU - Pawlikowski, Jeff
AU - Manoharan, Indrani
AU - Tuyn, John Van
AU - Nelson, David M.
AU - Singh Rai, Taranjit
AU - Shah, Parisha P.
AU - Hewitt, Graeme
AU - Korolchuk, Viktor I.
AU - Passos, Joao F.
AU - Wu, Hong
AU - Berger, Shelley L.
PY - 2013
Y1 - 2013
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84880585547&partnerID=8YFLogxK
U2 - 10.1083/jcb.201212110
DO - 10.1083/jcb.201212110
M3 - Article
C2 - 23816621
AN - SCOPUS:84880585547
SN - 0021-9525
VL - 202
SP - 129
EP - 143
JO - Journal of Cell Biology
JF - Journal of Cell Biology
IS - 1
ER -