Lysosome-mediated processing of chromatin in senescence

TLDR

Cellular senescence is a stable proliferation arrest that acts as a tumor suppressor and contributes to tissue aging, involving extensive remodeling of chromatin and relying on autophagy and lysosomes for cellular recycling. The study demonstrates that senescent cells use an autophagy/lysosomal pathway to process chromatin. In senescent cells, chromatin fragments bud from nuclei lacking lamin A/C, marked by γ‑H2AX and H3K27me3, as lamin B1 is down‑regulated and the nuclear envelope integrity is lost, and these fragments are then targeted by the autophagy machinery in the cytoplasm. Senescent cells exhibit lysosome‑dependent proteolytic degradation of histones, leading to progressive loss of total histone content that correlates with nevus maturation, supporting the idea that chromatin processing via autophagy/lysosomes contributes to senescence stability and tumor suppression.

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.