Reduce, Retain, Recycle: Mechanisms for Promoting Histone Protein Degradation versus Stability and Retention

Abstract

The eukaryotic genome is packaged into chromatin. The nucleosome, the basic unit of chromatin, is composed of DNA coiled around a histone octamer. Histones are among the longest-lived protein species in mammalian cells due to their thermodynamic stability and their associations with DNA and histone chaperones. Histone metabolism plays an integral role in homeostasis. While histones are largely stable, the degradation of histone proteins is necessary under specific conditions. Here, we review the physiological and cellular contexts that promote histone degradation. We describe specific known mechanisms that drive histone proteolysis. Finally, we discuss the importance of histone degradation and regulation of histone supply for organismal and cellular fitness.

Keywords: DNA replication; chaperone; chromatin; histone; nucleosome; nucleus; posttranslational modification; transcription.

FIG 1

Histone H3/H4 chaperones and homologs. Histone H3/H4 chaperone complexes are pictured in the leftmost column. The stage of H3/H4 complex with which they associate and preferences for H3 variants are indicated. The closest protein homolog from the budding yeast S. cerevisiae was identified using NCBI Homologene or NCBI BLAST.

FIG 2

Developmental contexts and mechanisms of histone degradation. (Spermiogenesis) Total core histones are acetylated and degraded during late spermiogenesis. Where known, specific acetylated residues are indicated. Following core histone degradation, DNA is complexed, first decompacted with transition proteins (yellow) and then highly compacted with protamines (purple). (Embryogenesis) Sperm-specific SpH2A is degraded by lysosomal CATL to allow cell cycle progression. Sperm-specific histones are replaced by zygotic histones. The degradation of sperm-specific H2B, H3, and H4 has not been evaluated. (Senescence) Cytoplasmic chromatin fragments containing histones colocalize with macroautophagy adapter p62, and total histone levels are lower in senescent cells. Histone-depleted DNA is transiently decondensed and then ultracondensed.

FIG 3

Cellular contexts and mechanisms of histone degradation. (Transcription) Total core histones are acetylated and lost following transcription induction. Where known, specific residues that are acetylated are indicated. The protein that degrades acetylated histones in this context is unknown. Total H3.3 and H3K4 are polyubiquitinated following transcription induction and then degraded by the 26S proteasome, which is necessary to facilitate transcription. (DNA repair) Total core histones are acetylated and degraded following DNA damage (lightning bolt). Where known, specific residues acetylated are indicated. The degradation of acetylated histones by the PA200 proteasome is necessary for DNA repair. (Histone oversupply) Excess soluble histones H3/H4 are generated by replication stress and then degraded by the lysosome through chaperone-mediated autophagy (CMA). Exogenous excess CENP-A^Cse4 is quickly degraded by the 26S proteasome.

FIG 4

ASF1 histone chaperone function during replication and replication stress. During normal replication, (i) soluble prenucleosomal H3/H4 complexes bearing H4K12ac are transferred from histone chaperones NASP to ASF1 and then to chromatin deposition complexes, and (ii) preexisting H3/H4 complexes bearing H3K9me3 are recycled at the replication fork by ASF1. Under replication stress, (i) ASF1 fails to transfer H3/H4K12ac to chromatin deposition complexes and shifts into a complex with NASP and excess soluble prenucleosomal H3/H4K12ac, and (ii) ASF1 fails to recycle H3K9me3/H4 and binds excess soluble preexisting histones. NASP binding to histones prevents lysosomal degradation of H3/H4 via chaperone-mediated autophagy (CMA).