Chromatin compartmentalization regulates the response to DNA damage
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB69680 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR12268200.fastq.gz | Fastqsanger.gz | |||
| ERR12268201.fastq.gz | Fastqsanger.gz | |||
| ERR12268202.fastq.gz | Fastqsanger.gz | |||
| ERR12268203.fastq.gz | Fastqsanger.gz | |||
| ERR12268204.fastq.gz | Fastqsanger.gz |
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Project description:DNA Double Strand Breaks (DSBs) repair is essential to safeguard genome integrity but little is known about the contribution of chromosome folding into these processes. Here we unveiled basic principles of chromosome dynamics occurring post-DSB both locally and at a genome wide scale in mammalian cells. We report that topologically associating domains (TAD) that experience a DSB undergo acute ATM-dependent but DNAPK- independent changes. Within these damaged TADs, DSB-induced loop extrusion ensures local transcriptional regulation in response to DSBs. Damaged TADs further coalesce in an ATM-dependent manner, forming a new “D” compartment, where upregulated genes of the DNA damage response (DDR) physically localize suggesting a function of DSB clustering in activating the DNA damage Response. However, these alterations of chromosome folding induced by DSB also come at the expense of an increased translocations rate. Our work highlights the critical impact of chromosome conformation in the maintenance of genome integrity.
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Project description:The DNA damage response is essential to safeguard genome integrity. Although the contribution of chromatin in DNA repair has been investigated1,2, the contribution of chromosome folding to these processes remains unclear3. Here we report that, after the production of double-stranded breaks (DSBs) in mammalian cells, ATM drives the formation of a new chromatin compartment (D compartment) through the clustering of damaged topologically associating domains, decorated with γH2AX and 53BP1. This compartment forms by a mechanism that is consistent with polymer-polymer phase separation rather than liquid-liquid phase separation. The D compartment arises mostly in G1 phase, is independent of cohesin and is enhanced after pharmacological inhibition of DNA-dependent protein kinase (DNA-PK) or R-loop accumulation. Importantly, R-loop-enriched DNA-damage-responsive genes physically localize to the D compartment, and this contributes to their optimal activation, providing a function for DSB clustering in the DNA damage response. However, DSB-induced chromosome reorganization comes at the expense of an increased rate of translocations, also observed in cancer genomes. Overall, we characterize how DSB-induced compartmentalization orchestrates the DNA damage response and highlight the critical impact of chromosome architecture in genomic instability.
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Project description:ING2 (inhibitor of growth family member 2) is a component of a chromatin-regulatory complex that represses gene expression and is implicated in cellular processes that promote tumor suppression. However, few direct genomic targets of ING2 have been identified and the mechanism(s) by which ING2 selectively regulates genes remains unknown. Here we provide evidence that direct association of ING2 with the nuclear phosphoinositide phosphatidylinositol-5-phosphate (PtdIns(5)P) regulates a subset of ING2 targets in response to DNA damage. At these target genes, the binding event between ING2 and PtdIns(5)P is required for ING2 promoter occupancy and ING2-associated gene repression. Moreover, depletion of PtdIns(5)P attenuates ING2-mediated regulation of these targets in the presence of DNA damage. Taken together, these findings support a model in which PtdIns(5)P functions as a sub-nuclear trafficking factor that stabilizes ING2 at discrete genomic sites. Genome-wide expression profiling of HT1080 cells stably transduced with ING2 or a ING2 lipid binding mutant in the presence of vehicle (DMSO) or etoposide. Each condition is tested in triplicate
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Project description:ING2 (inhibitor of growth family member 2) is a component of a chromatin-regulatory complex that represses gene expression and is implicated in cellular processes that promote tumor suppression. However, few direct genomic targets of ING2 have been identified and the mechanism(s) by which ING2 selectively regulates genes remains unknown. Here we provide evidence that direct association of ING2 with the nuclear phosphoinositide phosphatidylinositol-5-phosphate (PtdIns(5)P) regulates a subset of ING2 targets in response to DNA damage. At these target genes, the binding event between ING2 and PtdIns(5)P is required for ING2 promoter occupancy and ING2-associated gene repression. Moreover, depletion of PtdIns(5)P attenuates ING2-mediated regulation of these targets in the presence of DNA damage. Taken together, these findings support a model in which PtdIns(5)P functions as a sub-nuclear trafficking factor that stabilizes ING2 at discrete genomic sites. FLAG-ING2 ChIP-chip of stably-transduced HT1080 cells in the presence of vehicle (DMSO) or etoposide. Each condition is tested in duplicate.
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2015-03-16 | PXD001810 | Pride
Project description:DNA double strand break (DSB) repair depends on the ataxia telangiectasia mutated (ATM) kinase that phosphorylates the conserved C-terminal SQ motif present in the histone variant H2A.X [1-7]. In constitutive heterochromatin of mammals, DSB repair is delayed and relies on phosphorylation of the proteins HP1 and KAP1 by ATM [2, 8-14]. However, KAP1 is not conserved in plants and the HP1 related protein Like-HP1 (LHP1) is not localized at constitutive heterochromatin [15], suggesting that in plants, alternative mechanisms could be responsible for repair of DSBs in heterochromatin. In Arabidopsis, constitutive heterochromatin is marked by H3K9 methylation, and the plant-specific histone variants H2A.W which are distinguished by their C-terminal motif KSPKK and required for heterochromatin compaction [16-18]. We report that the Arabidopsis histone variant H2A.W.7 is confined to heterochromatin and carries a SQ motif that is phosphorylated by ATM. In response to DNA damage, phosphorylation of H2A.W.7 takes place in heterochromatin while H2A.X phosphorylation takes place primarily in euchromatin. We propose that H2A.W.7 evolved in addition to H2A.X to facilitate DNA damage response in highly condensed heterochromatin, thus playing a role similar to KAP1 and HP1 phosphorylation in mammals. These data support the idea of the functional diversification of histone variants and their role in spatial compartmentalization of chromatin related functions in eukaryotes.
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