Regulation of Histone Ubiquitination in Response to DNA Double Strand Breaks

Aquila, Lanni; Atanassov, Boyko S.

doi:10.3390/cells9071699

Cited by 31 publications

(17 citation statements)

References 193 publications

(368 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, H2AK119ub1 is highly dynamic (Seale 1981) and a number of deubiquitylating enzymes (DUBs) have been proposed to regulate its levels (reviewed in Belle and Nijnik 2014;Aquila and Atanassov 2020). The most extensively characterised and evolutionary conserved of these DUBs is BAP1, which interacts with ASXL proteins to form the Polycomb Repressive Deubiquitinase complex (PR-DUB) (Scheuermann et al 2010;Wu et al 2015;Sahtoe et al 2016;Kloet et al 2016;Hauri et al 2016;Campagne et al 2019).…”

Section: Introductionmentioning

confidence: 99%

BAP1 constrains pervasive H2AK119ub1 to control the transcriptional potential of the genome

Fursova

Turberfield

Blackledge

et al. 2020

Preprint

View full text Add to dashboard Cite

Histone-modifying systems play fundamental roles in gene regulation and the development of multicellular organisms. Histone modifications that are enriched at gene regulatory elements have been heavily studied, but the function of modifications that are found more broadly throughout the genome remains poorly understood. This is exemplified by histone H2A mono-ubiquitylation (H2AK119ub1) which is enriched at Polycomb-repressed gene promoters, but also covers the genome at lower levels. Here, using inducible genetic perturbations and quantitative genomics, we discover that the BAP1 deubiquitylase plays an essential role in constraining H2AK119ub1 throughout the genome. Removal of BAP1 leads to pervasive accumulation of H2AK119ub1, which causes widespread reductions in gene expression. We show that elevated H2AK119ub1 represses gene expression by counteracting transcription initiation from gene regulatory elements, causing reductions in transcription-associated histone modifications. Furthermore, failure to constrain pervasive H2AK119ub1 compromises Polycomb complex occupancy at a subset of Polycomb target genes leading to their derepression, therefore explaining the original genetic characterisation of BAP1 as a Polycomb group gene. Together, these observations reveal that the transcriptional potential of the genome can be modulated by regulating the levels of a pervasive histone modification, without the need for elaborate gene-specific targeting mechanisms.

show abstract

Section: Introductionmentioning

confidence: 99%

BAP1 constrains pervasive H2AK119ub1 to control the transcriptional potential of the genome

Fursova

Turberfield

Blackledge

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Interestingly, H2AK119ub1 is highly dynamic (Seale 1981), and a number of deubiquitylating enzymes (DUBs) have been proposed to regulate its levels (for review, see Belle and Nijnik 2014;Aquila and Atanassov 2020). The most extensively characterized and evolutionarily conserved of these DUBs is BAP1, which interacts with ASXL proteins to form the Polycomb repressive deubiquitinase complex (PR-DUB) (Scheuermann et al 2010;Wu et al 2015;Hauri et al 2016;Kloet et al 2016;Sahtoe et al 2016;Campagne et al 2019).…”

mentioning

confidence: 99%

BAP1 constrains pervasive H2AK119ub1 to control the transcriptional potential of the genome

et al. 2021

View full text Add to dashboard Cite

Histone-modifying systems play fundamental roles in gene regulation and the development of multicellular organisms. Histone modifications that are enriched at gene regulatory elements have been heavily studied, but the function of modifications found more broadly throughout the genome remains poorly understood. This is exemplified by histone H2A monoubiquitylation (H2AK119ub1), which is enriched at Polycomb-repressed gene promoters but also covers the genome at lower levels. Here, using inducible genetic perturbations and quantitative genomics, we found that the BAP1 deubiquitylase plays an essential role in constraining H2AK119ub1 throughout the genome. Removal of BAP1 leads to pervasive genome-wide accumulation of H2AK119ub1, which causes widespread reductions in gene expression. We show that elevated H2AK119ub1 preferentially counteracts Ser5 phosphorylation on the C-terminal domain of RNA polymerase II at gene regulatory elements and causes reductions in transcription and transcription-associated histone modifications. Furthermore, failure to constrain pervasive H2AK119ub1 compromises Polycomb complex occupancy at a subset of Polycomb target genes, which leads to their derepression, providing a potential molecular rationale for why the BAP1 ortholog in Drosophila has been characterized as a Polycomb group gene. Together, these observations reveal that the transcriptional potential of the genome can be modulated by regulating the levels of a pervasive histone modification.

show abstract

“…The current challenge is to disentangle indirect cellular effects from direct activities on substrates. Here, we discuss the case of USP51, in view of its latest and exciting findings, and refer elsewhere to the description of DUBs' activity in the DDR [5,104].…”

Section: Open Accessmentioning

confidence: 99%

Histone Ubiquitination: An Integrative Signaling Platform in Genome Stability

2021

View full text Add to dashboard Cite

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...

show abstract

Regulation of Histone Ubiquitination in Response to DNA Double Strand Breaks

Cited by 31 publications

References 193 publications

BAP1 constrains pervasive H2AK119ub1 to control the transcriptional potential of the genome

BAP1 constrains pervasive H2AK119ub1 to control the transcriptional potential of the genome

BAP1 constrains pervasive H2AK119ub1 to control the transcriptional potential of the genome

Histone Ubiquitination: An Integrative Signaling Platform in Genome Stability

Contact Info

Product

Resources

About