H4K20me0 recognition by BRCA1–BARD1 directs homologous recombination to sister chromatids

Nakamura, Kae; Saredi, Giulia; Becker, Jordan R.; Foster, Benjamin M.; Nguyen, Nhuong V.; Beyer, Tracey E.; Cesa, Laura C.; Faull, Peter; Lukauskas, Saulius; Frimurer, Thomas M.; Chapman, J. Ross; Bartke, Till; Groth, Anja

doi:10.1038/s41556-019-0282-9

Cited by 166 publications

(182 citation statements)

References 41 publications

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“…The choice between NHEJ and HR is closely linked to the cell cycle and to whether or not an undamaged homologous stretch of DNA is available as a template for HR [4][5][6] . While 53BP1-RIF1-Shieldin restrains DNA end resection of DNA double-strand breaks (DSBs) in the absence of a homologous template strand, after DNA replication BRCA1-BARD1 counteracts 53BP1 binding to damaged chromatin and promotes HR reactions [7][8][9][10][11][12] . The antagonism between 53BP1-RIF1-Shieldin and BRCA1-BARD1 has important implications for cancer therapy, in particular for targeting BRCA-deficient tumors with PARP inhibitors, and for improving CRISPR/Cas9-mediated gene editing.…”

Section: Introductionmentioning

confidence: 99%

“…Accumulating evidence suggests that this discrimination is linked to the different chromatin makeup ahead of and behind replication forks [10][11][12][13][14] . Of particular interest for the antagonism between the 53BP1 and BRCA1 protein complexes is the H4K20 dimethylation mark (H4K20me2), which is abundant in unreplicated chromatin on parental histones and absent from newly incorporated histones.…”

Section: Introductionmentioning

confidence: 99%

“…Of particular interest for the antagonism between the 53BP1 and BRCA1 protein complexes is the H4K20 dimethylation mark (H4K20me2), which is abundant in unreplicated chromatin on parental histones and absent from newly incorporated histones. Hence H4K20me2 is diluted in nascent replicated chromatin and only restored in mature chromatin in late G2/M [10][11][12][13][14] . 53BP1 binds H4K20me2 via its tandem tudor domain (TTD), and both H4K20me2 and the TTD are required for 53BP1 recruitment to DSBs 15,16 .…”

Section: Introductionmentioning

confidence: 99%

“…53BP1 binds H4K20me2 via its tandem tudor domain (TTD), and both H4K20me2 and the TTD are required for 53BP1 recruitment to DSBs 15,16 . Conversely, unmethylated H4K20 (H4K20me0) in replicated chromatin is recognized by the HR-promoting protein complexes TONSL-MMS22L and BRCA1-BARD1 12,14 .…”

Section: Introductionmentioning

confidence: 99%

“…It was recently established that the ankyrin repeat domain (ARD) of BARD1 binds to H4K20me0 and brings the BRCA1-BARD1 complex to DNA breaks when a sister chromatid is available for DSB repair by HR, thus illuminating the mechanistic underpinnings of BRCA1-mediated displacement of 53BP1 from replicated chromatin 12 . An unresolved question is, however, whether the antagonism between BRCA1-BARD1 and 53BP1 alone is sufficient to explain the displacement of 53BP1 from damaged replicated chromatin, or whether the dilution of H4K20me2 behind replication forks directly impacts 53BP1 recruitment and thereby affects its functions even when BRCA1-BARD1 functions are impaired.…”

Section: Introductionmentioning

confidence: 99%

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Replicated chromatin curtails 53BP1 recruitment in BRCA1-proficient and -deficient cells

Mitxelena

Pellegrino

Spegg

et al. 2020

Preprint

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DNA double-strand breaks can be repaired by two competing mechanisms, nonhomologous end-joining (NHEJ) and homologous recombination (HR). Whether one or the other repair pathway is favored depends on the availability of an undamaged template DNA that allows for homology-directed repair. The tumor suppressor proteins 53BP1 and BRCA1 are considered antagonistic players in this repair pathway choice, as 53BP1 restrains DNA end resection, whereas BRCA1, together with its partner protein BARD1, displaces 53BP1 from damaged replicated chromatin and promotes HR. How cells switch from a 53BP1-dominated to a BRCA1-dominated response as they progress through the cell cycle is incompletely understood. Here we reveal, using high-throughput microscopy and applying single cell normalization to control for increased genome size as cells replicate their DNA, that 53BP1 recruitment to damaged replicated chromatin is inefficient in both BRCA1-proficient and BRCA1-deficient cells, in comparison to 53BP1 accumulation at damaged unreplicated chromatin. These findings substantiate a dual switch model from a 53BP1-dominated response in unreplicated chromatin to a BRCA1-BARD1-dominated response in replicated chromatin, in which replication-coupled dilution of 53BP1's binding mark H4K20me2 functionally cooperates with BRCA1-BARD1mediated suppression of 53BP1 binding. More generally, we suggest that appropriate normalization of single cell data, e.g. to DNA content, provides additional layers of information, which can be critical for quantifying and interpreting cellular phenotypes.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Replicated chromatin curtails 53BP1 recruitment in BRCA1-proficient and -deficient cells

Mitxelena

Pellegrino

Spegg

et al. 2020

Preprint

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STAG2 Regulates Homologous Recombination Repair and Sensitivity to ATM Inhibition

Zhou,

Nie,

et al. 2023

Advanced Science

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Stromal antigen 2 (STAG2), a subunit of the cohesin complex, is recurrently mutated in various tumors. However, the role of STAG2 in DNA repair and its therapeutic implications are largely unknown. Here it is reported that knockout of STAG2 results in increased double‐stranded breaks (DSBs) and chromosomal aberrations by reducing homologous recombination (HR) repair, and confers hypersensitivity to inhibitors of ataxia telangiectasia mutated (ATMi), Poly ADP Ribose Polymerase (PARPi), or the combination of both. Of note, the impaired HR by STAG2‐deficiency is mainly attributed to the restored expression of KMT5A, which in turn methylates H4K20 (H4K20me0) to H4K20me1 and thereby decreases the recruitment of BRCA1‐BARD1 to chromatin. Importantly, STAG2 expression correlates with poor prognosis of cancer patients. STAG2 is identified as an important regulator of HR and a potential therapeutic strategy for STAG2‐mutant tumors is elucidated.

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Epigenotoxicity: Decoding the epigenetic imprints of genotoxic agents and their implications for regulatory genetic toxicology

Godschalk,

Faulk,

LaRocca

et al. 2024

Environ and Mol Mutagen

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Regulatory genetic toxicology focuses on DNA damage and subsequent gene mutations. However, genotoxic agents can also affect epigenetic marks, and incorporation of epigenetic data into the regulatory framework may thus enhance the accuracy of risk assessment. Additionally, epigenetic alterations may identify non‐genotoxic carcinogens that are not captured with the current battery of tests. Epigenetic alterations could also explain long‐term consequences and potential transgenerational effects in the absence of DNA mutations. Therefore, at the 2022 International Workshops on Genotoxicity Testing (IWGT) in Ottawa (Ontario, Canada), an expert workgroup explored whether including epigenetic endpoints would improve regulatory genetic toxicology. Here we summarize the presentations and the discussions on technical advancements in assessing epigenetics, how the assessment of epigenetics can enhance strategies for detecting genotoxic and non‐genotoxic carcinogens and the correlation between epigenetic alterations with other relevant apical endpoints.

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H4K20me0 recognition by BRCA1–BARD1 directs homologous recombination to sister chromatids

Cited by 166 publications

References 41 publications

Replicated chromatin curtails 53BP1 recruitment in BRCA1-proficient and -deficient cells

Replicated chromatin curtails 53BP1 recruitment in BRCA1-proficient and -deficient cells

STAG2 Regulates Homologous Recombination Repair and Sensitivity to ATM Inhibition

Epigenotoxicity: Decoding the epigenetic imprints of genotoxic agents and their implications for regulatory genetic toxicology

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