Histone Ubiquitination: An Integrative Signaling Platform in Genome Stability

Histones are heavily post-translationally modified by ubiquitin. Lately, many more ubiquitin-based modifications have been mapped on histones, which far less abundant than the canonical ones but essential to safeguard genome stability.Histones at damaged DNA can be phospho-ubiquitin (i.e., pUb Thr12), resulting in chromatin regions with new properties that impact repair pathways.The discovery of ubiquitination sites histones and ubiquitin expands dramatically landscape chromatin-based signaling crosstalk, paving way for future studies novel mechanisms stability programs writers, readers, erasers). Complex place maintain stability. Ubiquitination plays a central role these mechanisms. The ever-growing complexity (Ub) code dynamics challenges our ability fully understand how histone regulates Here we review current knowledge specific, low-abundant events highly regulated within cellular damage response (DDR), particular emphasis latest Ub phosphorylation as regulator DDR pathway. We discuss players involved potential implications (phospho)ubiquitination structure, highlight exciting open questions research. Complexity Histone EventsHistone differs substantially from other post-translational (PTMs) small chemical groups because it entails covalent binding 76–amino acid protein; is, is result sequential actions E1 activating, E2 conjugating, E3 ligase enzymes, yielding conjugation lysine (Lys) residue proteins, or itself form different flavors polyUb chains [1.Oh E. et al.Principles ubiquitin-dependent signaling.Annu. Rev. Cell Dev. Biol. 2018; 34: 137-162Crossref PubMed Scopus (75) Google Scholar, 2.Swatek K.N. Komander D. Ubiquitin modifications.Cell Res. 2016; 26: 399-422Crossref (541) 3.Kliza K. Husnjak Resolving networks.Front. Mol. Biosci. 2020; 7: 21Crossref (2) Scholar]. In parallel, deubiqutinating enzymes (DUBs) responsible removal marks [4.Mevissen T.E.T. Mechanisms deubiquitinase specificity regulation.Annu. Biochem. 2017; 86: 159-192Crossref (295) system was further increased Ub-like modifiers (UbLs) PTMs target create an exponentially complex (Figure 1 Box 1).Box 1Histone Modifications UbLsUbLs closely resemble fold I), due their divergent sequence (indicated percentage homology compared Ub), they exert specific functions when conjugated substrate proteins. UbL requires specialized E1-E2-E3 generally function through similar [111.Cappadocia L. Lima C.D. Ubiquitin-like protein conjugation: structures, chemistry, mechanism.Chem. 118: 889-918Crossref (131) modification UbLs has recently described. SUMO [112.Nathan al.Histone sumoylation negative Saccharomyces cerevisiae shows dynamic interplay positive-acting modifications.Genes 2006; 20: 966-976Crossref (243) 113.Dhall A. al.Sumoylated human H4 prevents compaction inhibiting long-range internucleosomal interactions.J. 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Jentsch Protein synergy pathway exemplified repair.Cell. 2012; 151: 807-820Abstract (292) Scholar].Figure IUb-like Proteins Involved Modification.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Histones among most monoubiquitinated 5–15% 1% H2B, leading H2AK118/119ub H2BK120ub, respectively. recent years, appeared undergo modifications, recognized orchestrating fundamental processes [5.Uckelmann M. Sixma T.K. response.DNA Repair (Amst). 56: 92-101Crossref (0) 2A ). this review, examine data ubiquitination, highlighting identified noncanonical context last part, present concept its effect ubiquitinated chromatin, promises bring intriguing directions research biology.Figure 2Roles Different Damage Response (DDR).Show full caption(A) Schematic representation H1-bound nucleosome carrying H2A, H1 linker. H2B functional effects indicated. K63-linked (blue circles). (B) composed (H3-H4)2 tetramer (gray) two H2A-H2B dimers (H2A yellow, red), wrapped 150 bp (white). (in sand) interacts dyad. shown dark blue. Canonical H2AK118/119 lie nearby dyad, preceding H2AK125/127/129 flexible C-terminal tail (not visible crystal here schematic line). On opposite sides nucleosome, H2AK13/15 close proximity H2BK120. (PDB 5NL0). (C) Flexibility moiety allows both H2AK13/15ub (dark blue) H2BK120ub (light present. However, simultaneously signal remains question. Superposition H2AK15ub-NCP: PDB 5KGF, 53BP1 fragment shown. H2BK120ub: 6NJ9, DOT1L, shown.View (PPT)Histone Genotoxic StressUnscheduled alterations consequence damage, elicit rapid response, promoting variety react resolve potentially harmful situation. These cascade involving factors able sense lesion, halt pathways (e.g., cell cycle, transcription), resume thereafter. 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Open table tab H2BIn mammals, (H2Bub) Lys120 (H2BK120ub; 2) heterodimeric RNF20/RNF40. elongation, also promoted agents [8.Moyal interfere fibers vitro [11.Fierz Scholar]; therefore, promote opening lesions. results accumulation DSBs, suggesting early before cells commit Interestingly, conserved yeast, where Lys123 (H2BK123ub) [12.Zheng Scholar].In H2BK123ub (see Glossary) [13.Hung hist