BARD1 links histone H2A Lysine-15 ubiquitination to initiation of BRCA1-dependent homologous recombination

Becker, Jordan R.; Bonnet, Clara; Clifford, Gillian; Groth, Anja; Wilson, Marcus D.; Chapman, J. Ross

doi:10.1101/2020.06.01.127951

Cited by 15 publications

(26 citation statements)

References 36 publications

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“…BARD1, also bearing two BRCT domains at its C-terminus, has been shown to be critical for the mobilization of the heterodimer to DNA damaged sites by recognizing PAR molecules at DNA lesions, regardless of the H2AX status ( 98 ). Recently, it has been reported that BARD1 was able to bind ubiquitylated H2A at lysine 15 directly through its BUDR (BRCT domain ubiquitin-dependent recruitment) motif and this occurred synergistically with the binding of its ankyrin repeat domain (ARD) to H4K20me0, generating a strong interaction between damaged chromatin and BARD1 in S and G2 phases ( 87 ).…”

Section: Brca1: Safeguard Of the Genomementioning

confidence: 99%

Untangling the crosstalk between BRCA1 and R-loops during DNA repair

Alonso

Noordermeer

2021

Nucleic Acids Research

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R-loops are RNA:DNA hybrids assembled during biological processes but are also linked to genetic instability when formed out of their natural context. Emerging evidence suggests that the repair of DNA double-strand breaks requires the formation of a transient R-loop, which eventually must be removed to guarantee a correct repair process. The multifaceted BRCA1 protein has been shown to be recruited at this specific break-induced R-loop, and it facilitates mechanisms in order to regulate R-loop removal. In this review, we discuss the different potential roles of BRCA1 in R-loop homeostasis during DNA repair and how these processes ensure faithful DSB repair.

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Section: Brca1: Safeguard Of the Genomementioning

confidence: 99%

Untangling the crosstalk between BRCA1 and R-loops during DNA repair

Alonso

Noordermeer

2021

Nucleic Acids Research

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“…Very recently, BARD1 has also been suggested to recognize H2AK15ub in human cells [83], highlighting a possible Ub reader-writer crosstalk between N-and C-terminal H2A Ub marks, which should be further explored and characterized.…”

Section: Readers and Consequences Of H2a Ubiquitination At K13/15mentioning

confidence: 99%

Histone Ubiquitination: An Integrative Signaling Platform in Genome Stability

2021

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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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“…A recent study revealed that BARD1 localizes to DNA damage sites through a dual mechanism involving both the ANK and BRCT domains 26 . The BARD1 ANK domain is a reader of histone H4 unmethylated at K20 (H4K20me0) 17 , and the BRCT repeat was shown to contain a BRCT domain ubiquitin-dependent recruitment motif (BUDR), which directly binds mUb-H2A 26 . Indeed, MCF7 BARD1 -/cells engineered to express a BARD1 BUDR mutant construct (Fig.…”

Section: S3d)mentioning

confidence: 99%

“…In the current study, we report an RNF168-governed pathway that is responsible for the recruitment of the BRCA1-P complex to DSBs. A BUDR was recently discovered within the BARD1 BRCT domain, which directly binds mUb-H2A 26 . In support of this, mutating residues within the BUDR, or specifically blocking the ability of RNF168 to generate mUb-H2A, reduced BRCA1-P complex recruitment to DSBs.…”

Section: S3d)mentioning

confidence: 99%

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RNF168-mediated localization of BARD1 recruits the BRCA1-PALB2 complex to DNA damage

Krais

Wang

Patel

et al. 2021

Preprint

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DNA damage prompts a diverse range of alterations to the chromatin landscape. The RNF168 E3 ubiquitin ligase catalyzes the mono-ubiquitination of histone H2A at lysine (K)13/15 (mUb-H2A), forming a binding module for DNA repair proteins. BRCA1 promotes homologous recombination (HR), in part, through its interaction with PALB2, and the formation of a larger BRCA1-PALB2-BRCA2-RAD51 (BRCA1-P) complex. The mechanism by which BRCA1-P is recruited to chromatin surrounding DNA breaks is unclear. In this study, we reveal that an RNF168-governed signaling pathway is responsible for localizing the BRCA1-P complex to DNA damage. Using mice harboring a Brca1CC (coiled coil) mutation that blocks the Brca1-Palb2 interaction, we uncovered an epistatic relationship between Rnf168- and Brca1CC alleles, which disrupted development, and reduced the efficiency of Palb2-Rad51 localization. Mechanistically, we show that RNF168-generated mUb-H2A recruits BARD1 through a BRCT domain ubiquitin-dependent recruitment motif (BUDR). Subsequently, BARD1-BRCA1 accumulate PALB2-RAD51 at DNA breaks via the CC domain-mediated BRCA1-PALB2 interaction. Together, these findings establish a series of molecular interactions that connect the DNA damage signaling and HR repair machinery.

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BARD1 links histone H2A Lysine-15 ubiquitination to initiation of BRCA1-dependent homologous recombination

Cited by 15 publications

References 36 publications

Untangling the crosstalk between BRCA1 and R-loops during DNA repair

Untangling the crosstalk between BRCA1 and R-loops during DNA repair

Histone Ubiquitination: An Integrative Signaling Platform in Genome Stability

RNF168-mediated localization of BARD1 recruits the BRCA1-PALB2 complex to DNA damage

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