HPF1-dependent histone ADP-ribosylation triggers chromatin relaxation to promote the recruitment of repair factors at sites of DNA damage

Smith, Rebecca; Zentout, Siham; Rother, Magdalena B.; Bigot, Nicolas; Chapuis, Catherine; Mihuț, Alexandra; Zobel, Florian; Ahel, Ivan; Attikum, Haico van; Timinszky, Gyula; Huet, Sébastien

doi:10.1038/s41594-023-00977-x

Cited by 28 publications

(18 citation statements)

References 55 publications

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“…We demonstrate that they both contribute to bookmark damaged chromatin during a crucial stage of the cell cycle by interfering with H3 mitotic phosphorylation. This function of histone ADP-ribosylation is likely distinct from its recently reported role in promoting chromatin relaxation at DNA double-strand breaks in human cells 24 . We provide evidence for a direct interference between ADPr and phosphorylation on H3S10 and the same likely applies to H3S28 because those two residues are the main targets of damage-induced ADPr 21 .…”

Section: Discussionmentioning

confidence: 56%

“…Inhibition (Figure 3B) or knock-down (Figure S4C) of PARP enzymes abrogated the H3S10ph defect in cells damaged just before mitosis, revealing an early inhibitory effect of ADPr on H3S10ph at UV sites. Similarly, knocking-down the PARP cofactor HPF1, that regulates histone ADP-ribosylation in response to DNA damage 24 , reduced H3S10ph defect at UV sites (Figure S4D), indicating that PARP and HPF1 act in concert to inhibit H3S10ph deposition in UV-damaged chromatin. Reciprocally, maintaining ADPr by inhibiting Poly(ADP-ribose) glycohydrolase (PARG) or by depleting ADP ribosylhydrolase 3 (ARH3), which specifically targets serine residues 19,25 , led to a prolonged H3S10ph defect at UV sites, detectable in cells irradiated 3h before mitosis (Figure 3C and Figure S4E).…”

Section: Resultsmentioning

confidence: 89%

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Mitotic chromatin marking governs asymmetric segregation of DNA damage

Ferrand,

Dabin,

Chevallier

et al. 2023

Preprint

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The faithful segregation of intact genetic material and the perpetuation of chromatin states through mitotic cell divisions are pivotal for maintaining cell function and identity across cell generations. However, most exogenous mutagens generate long-lasting DNA lesions that are segregated during mitosis. How this segregation is controlled is unknown. Here, we uncover a mitotic chromatin-marking pathway that governs the segregation of UV-induced damage in human cells. Our mechanistic analyses reveal two layers of control: histone ADP-ribosylation, and the incorporation of newly synthesized histones at UV damage sites, that both prevent local mitotic phosphorylations on histone H3 serines. Functionally, this chromatin-marking pathway drives the asymmetric segregation of UV damage in the cell progeny with potential consequences on daughter cell fate. We propose that this mechanism may help preserve the integrity of stem cell compartments during asymmetric cell divisions.

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Section: Discussionmentioning

confidence: 56%

Section: Resultsmentioning

confidence: 89%

Mitotic chromatin marking governs asymmetric segregation of DNA damage

Ferrand,

Dabin,

Chevallier

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Interestingly, the recruitments of PARP1 and HPF1 to DNA breaks are unique, with PARP1 arriving first and HPF1 arriving later. 5 These data suggest temporally distinct MAR- and PAR-dependent pathways may exist during strand break repair, involving PARP1/HPF1 and PARP1 alone, respectively. However, this hypothesis was previously untestable due to the lack of reagents differentiating between MAR and PAR.…”

Section: Main Textmentioning

confidence: 81%

Molecular tools unveil distinct waves of ADP-ribosylation during DNA repair

Dasovich

Leung

2023

Cell Reports Methods

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“…The chromatin relaxation assay was performed as in (Smith et al, 2023). This assay uses PAGFP tagged histone H2B to mark a chromatin region by local photoactivation.…”

Section: Chromatin Relaxation and Dna Accessibility Assaymentioning

confidence: 99%

“…BZIP DNA domain from C/EBPa transcription factor was fused to GFP (Smith et al, 2023). Cells were transiently transfected and subjected to laser micro-irradiation and monitored BZIP-GFP recruitment to DSBs in control and siGATAD2B cells.…”

Section: Chromatin Relaxation and Dna Accessibility Assaymentioning

confidence: 99%

GATAD2B containing NuRD complex drives R-loop dependent chromatin boundary formation at double strand breaks

Liu,

Ajit,

et al. 2024

Preprint

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Double-strand breaks (DSBs) are the most lethal form of DNA damage. Transcriptional activity at DSBs, as well as transcriptional repression around DSBs, are both required for efficient DNA repair. The chromatin landscape defines and coordinates these two opposing events. However, the regulation of the open and condensed chromatin architecture is still unclear. In this study, we show that the GATAD2B-NuRD complex associates with DSBs in a transcription- and R-loop-dependent manner, to promote histone deacetylation and chromatin condensation, creating a temporal boundary between open and closed chromatin. This boundary is necessary for correct DNA end resection termination. The lack of the GATAD2B-NuRD complex leads to chromatin hyper-relaxation and extended DNA end resection, resulting in HR repair failure. Our results suggest that the GATAD2B-NuRD complex is a key coordinator of the dynamic interplay between transcription and chromatin landscape and underscore its biological significance in the RNA-dependent DNA damage response.

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HPF1-dependent histone ADP-ribosylation triggers chromatin relaxation to promote the recruitment of repair factors at sites of DNA damage

Cited by 28 publications

References 55 publications

Mitotic chromatin marking governs asymmetric segregation of DNA damage

Mitotic chromatin marking governs asymmetric segregation of DNA damage

Molecular tools unveil distinct waves of ADP-ribosylation during DNA repair

GATAD2B containing NuRD complex drives R-loop dependent chromatin boundary formation at double strand breaks

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