Histone proteolysis: A proposal for categorization into ‘clipping’ and ‘degradation’

Abstract

We propose for the first time to divide histone proteolysis into “histone degradation” and the epigenetically connoted “histone clipping”. Our initial observation is that these two different classes are very hard to distinguish both experimentally and biologically, because they can both be mediated by the same enzymes. Since the first report decades ago, proteolysis has been found in a broad spectrum of eukaryotic organisms. However, the authors often not clearly distinguish or determine whether degradation or clipping was studied. Given the importance of histone modifications in epigenetic regulation we further elaborate on the different ways in which histone proteolysis could play a role in epigenetics. Finally, unanticipated histone proteolysis has probably left a mark on many studies of histones in the past. In conclusion, we emphasize the significance of reviving the study of histone proteolysis both from a biological and an experimental perspective.

Analyses of Histone Proteoforms Using Front-end Electron Transfer Dissociation-enabled Orbitrap Instruments

“…This area of study is clearly poised for significant expansion, as evidenced by the identification of two H2A-specific proteases and several novel histone clipping events in just the past few years (39 -42). Discerning whether any histonecleaving event is the result of continuous histone turnover or sample degradation versus an alternative biological process with epigenetic implications is challenging (36). Our in vitro data suggest that cathepsin L might be a potential candidate to explain some of the truncated histone H2A proteoforms we observed in the butyrate-treated HeLa cell histone samples.…”

Clipping of arginine-methylated histone tails by JMJD5 and JMJD7

“…Kouzarides and colleagues also reported that an endopeptidase in Saccharomyces cerevisiae cleaves the first 21 residues from H3 (47). A number of groups have reported different candidate enzymes responsible for the cleavage of histone tails (4,5). However, systematic characterization of the enzyme family(ies) responsible for this activity has been lacking.…”

“…Most importantly, the biological significance of this modification is not well understood. It has been suggested that the proteolytic cleavage of histone tails plays critical roles in a variety of processes, including control of the cell cycle, development, response to infection, embryonic stem cell differentiation, aging, spermatogenesis, and sporulation (4,5). Due to the diversity of histone tail modifications, a critical question is whether a family of proteases specifically recognizes individual modified histone tails in different contexts, similar to other histonemodifying enzyme families.…”

“…However, despite the confirmed importance of methylation of histone arginines in transcriptional regulation (2), the question of whether arginine methylation is reversible is unsolved and controversial. On the other hand, the phenomenon of clipping of histone tails has been reported and has received significant attention in recent years (3)(4)(5). However, unlike other epigenetic modifications, no enzyme family has been determined to be responsible for histone clipping, although potential individual enzyme candidates have been implicated in this mechanism (3)(4)(5).…”

Top-down and Middle-down Protein Analysis Reveals that Intact and Clipped Human Histones Differ in Post-translational Modification Patterns*

“…Post translational modifications (PTMs) 1 of histones play a major role in regulation of chromatin functionality. Evidence is emerging that not only "classical" histone PTMs, such as methylation, acetylation, and phosphorylation at distinct residues, but also proteolytic processing of nucleosome proteins, known as "histone clipping," can be involved in regulation of key cellular processes, such as transcriptional regulation, cell differentiation, and senescence (1)(2)(3)(4)(5)(6)(7).…”