PA200-Mediated Proteasomal Protein Degradation and Regulation of Cellular Senescence

Abstract

Cellular senescence is closely related to DNA damage, proteasome inactivity, histone loss, epigenetic alterations, and tumorigenesis. The mammalian proteasome activator PA200 (also referred to as PSME4) or its yeast ortholog Blm10 promotes the acetylation-dependent degradation of the core histones during transcription, DNA repair, and spermatogenesis. According to recent studies, PA200 plays an important role in senescence, probably because of its role in promoting the degradation of the core histones. Loss of PA200 or Blm10 is a major cause of the decrease in proteasome activity during senescence. In this paper, recent research progress on the association of PA200 with cellular senescence is summarized, and the potential of PA200 to serve as a therapeutic target in age-related diseases is discussed.

Keywords: Blm10; PA200; PSME4; aging; proteasome; protein degradation; senescence.

Figure 1

Structures of proteasomes. (A), 20S CP (PDB ID: 7PG9) (B), 26S proteasome (PDB ID:6MSH) (C), and the PA28 proteasome (PDB ID:7NAO) include the PA28αβ proteasome and the PA28γ proteasome. (D), PA200 proteasome (PDB ID: 6KWY) (E), the BRDL-domain of PA200 (PDB ID: 6KWX). Structural data from the PDB database.

Figure 2

Scheme for the proposed mechanisms by which the PA200-proteasome regulates cellular senescence.