Histone Ubiquitination: An Integrative Signaling Platform in Genome Stability

Abstract

Complex mechanisms are in place to maintain genome stability. Ubiquitination of chromatin plays a central role in these mechanisms. The ever-growing complexity of the ubiquitin (Ub) code and of chromatin modifications and dynamics challenges our ability to fully understand how histone ubiquitination regulates genome stability. Here we review the current knowledge on specific, low-abundant histone ubiquitination events that are highly regulated within the cellular DNA damage response (DDR), with particular emphasis on the latest discovery of Ub phosphorylation as a novel regulator of the DDR signaling pathway. We discuss players involved and potential implications of histone (phospho)ubiquitination on chromatin structure, and we highlight exciting open questions for future research. The Complexity of Histone Ubiquitination EventsHistone ubiquitination differs substantially from the other histone post-translational modifications (PTMs) by small chemical groups because it entails the covalent binding of a 76-amino acid protein; that is, ubiquitination is the result of sequential actions of E1 activating, E2 conjugating, and E3 ligase enzymes, yielding the covalent conjugation of ubiquitin (Ub) to a lysine (Lys) residue on proteins, or on Ub itself to form different flavors of polyUb chains [1-3]. In parallel, deubiqutinating enzymes (DUBs) are responsible for the removal of these Ub marks [4]. The complexity of the Ub system was further increased by the discovery that Ub-like modifiers (UbLs) and PTMs target Ub to create an exponentially complex Ub code (Figure 1 and Box 1).Histones are among the most abundant monoubiquitinated proteins, with 5-15% of H2A and 1% of H2B, leading to H2AK118/119ub and H2BK120ub, respectively. In recent years, it appeared that histones undergo many other Ub modifications, which are far less abundant than the canonical H2AK118/119ub or H2BK120ub, but recognized as essential players in orchestrating fundamental processes on chromatin [5] (Figure 2A). In this review, we examine the most recent data on histone ubiquitination, highlighting the impact of the recently identified noncanonical modifications in the context of genome stability. In the last part, we present and discuss the new concept of Ub phosphorylation and its effect on ubiquitinated chromatin, which promises to bring intriguing new directions for future research in chromatin and Ub biology. Histone Ubiquitination in Response to Genotoxic StressUnscheduled alterations to the DNA structure, as a consequence of DNA damage, elicit a rapid chromatin response, promoting a variety of histone PTMs that are in place to react to and resolve the potentially harmful situation. These events are part of the DDR, a signaling cascade involving many factors able to sense the lesion, to halt cellular pathways (e.g., cell cycle, transcription), to repair the damage, and to resume cellular processes thereafter. Similar events occur in response to stress, such as during perturbed DNA replication or at dysfunctional telomeres, when DNA structure in...

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