Proteasome activator PA200 maintains stability of histone marks during transcription and aging

Abstract

The epigenetic inheritance relies on stability of histone marks, but various diseases, including aging-related diseases, are usually associated with alterations of histone marks. How the stability of histone marks is maintained still remains unclear. The core histones can be degraded by the atypical proteasome, which contains the proteasome activator PA200, in an acetylation-dependent manner during somatic DNA damage response and spermiogenesis.Here we show that PA200 promotes the transcription-coupled degradation of the core histones, and plays an important role in maintaining the stability of histone marks. Degradation of the histone variant H3.3, which is incorporated into chromatin during transcription, was much faster than that of its canonical form H3.1, which is incorporated during DNA replication. This degradation of the core histones could be suppressed by the transcription inhibitor, the proteasome inhibitor or deletion of PA200. The histone deacetylase inhibitor accelerated the degradation rates of H3 in general, especially its variant H3.3, while the mutations of the putative acetyl-lysine-binding region of PA200 abolished histone degradation in the G1-arrested cells, supporting that acetylation is involved in the degradation of the core histones. Deletion of PA200 dramatically altered deposition of the active transcriptional hallmarks (H3K4me3 and H3K56ac) and transcription, especially during cellular aging. Furthermore, deletion of PA200 or its yeast ortholog Blm10 accelerated cellular aging. Notably, the PA200-deficient mice displayed a range of aging-related deteriorations, including immune malfunction, anxiety-like behaviors and shorter lifespan. Thus, the proteasome activator PA200 is critical to the maintenance of the stability of histone marks during transcription and aging. 3

Histone degradation by the proteasome regulates chromatin and cellular plasticity

“…Such association of acetylated histones with open regions of the chromatin can perhaps account for their susceptibility to degradation. Indeed, the degradation of acetylated histones by PA200-capped proteasomes was suggested to be coupled to transcription, and to affect the stability of the total populations of histone variant H3.3 and core histone H4, probably during histone exchange [24]. Yet, it is still unclear what initiates this process and to what extent PA200 plays an active part in it.…”

“…For example, under normal conditions, the arginine methyl transferase PRMT1 mediates symmetrical dimethylation of H4 on arginine in position 3 (H4R3me2as), which maintains histone H4 stability. Exposure of cells to oxidative stress, DNA damage, or hyperoncogenic signaling pressure (associated with senescence) leads to a reduction in PRMT1-mediated H4R3me2, promoting the ubiquitin-independent degradation of H4 by PA200-capped proteasomes [23,75]. Degradation of H4 thereby reduces nucleosomal occupancy and affects cell proliferation by promoting the transcription of cell cycle inhibitors, senescence-associated genes, and regulators of apoptosis [75].…”

“…These were followed by a latent era in the field until the discovery of protease-dependent histone clipping and their potential involvement in epigenetic regulation [30][31][32], which reinvigorated the importance of histone proteolysis. Since then, major advances were achieved in the understanding of regulated histone degradation in cellular contexts by the two major selective degradation pathways of intracellular proteins, namely the proteasome and lysosome systems [18][19][20][21][22][23][24]33,34], which provide high specificity, selectivity, and fine-tuning capabilities of protein abundance [35].…”

“…Accumulation of an unbound histone pool may occur under various conditions including hyper-active chromatin-transacting processes that involve histone eviction like transcriptional changes, developmental transitions, response to DNA damage or damage to histones themselves as well as imbalanced histone levels during S-phase [15,18]. Further, histone degradation is emerging as a main regulatory step in the fine-tuned reorganization of chromatin architecture in response to developmental and environmental cues, and in response to cellular stress [19][20][21][22][23][24][25]. Taken together, tight regulation of the histone pool by degradation serves to both balance the changes in histone levels and chromatin binding to prevent toxicity, as well as to modulate the chromatin by tweaking histone levels.…”

Research progress and prospect of aging mechanism and anti-aging

“…For example, the sirtuin family of proteins, which is related to many aging-related physiological processes, can work with proteins such as p53, NF-kB, forkhead box O, PGC-1, and mTOR to regulate the stress response and thus affect the aging process. Han Xia et al [14] reported that PA200-proteasome could maintain the stability of histone code by mediating the histone degradation process. The histone acetyltransferase encoded by gene KAT7 [15], which was discovered last year, also belongs to class III.…”