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ID3 Deficiency Alters Chromatin Accessibility at DSB Sites and Enhances Vulnerability to HDAC Inhibition [RNA-seq]

ABSTRACT: The inhibitor of DNA-binding 3 (ID3) plays a crucial role in DNA double-strand break (DSB) repair. We previously reported that ID3 loss reduced chromatin accessibility at DNA repair gene promoters, yet its exact role in DNA repair via chromatin regulation remained elusive. Using the AID-DIvA cell system with inducible DSBs, we show that ID3 directly regulates chromatin accessibility at DSB sites, as demonstrated by reduced chromatin accessibility and lower H3K27ac levels in ID3-knockout (KO) cells. Loss of ID3 renders cells highly sensitive to histone deacetylase (HDAC) inhibition, particularly to the Class I HDAC inhibitor, leading to the accumulation of unrepaired DSBs and delayed cell cycle progression. Transcriptome and proteome analyses revealed that HDAC inhibition in ID3-KO cells results in the downregulation of gene sets involved in the regulation of cell cycle and cell division. The synthetic lethality observed between ID3 loss and Class I HDAC inhibition underscores a novel therapeutic vulnerability in ID3-deficient cancers, driven by compounded defects in chromatin remodeling, cell cycle, and DNA repair. Our study provides new insights into the relationship between chromatin regulation and genome stability, with implications for targeted cancer therapies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE301513 | GEO | 2026/01/29

REPOSITORIES: GEO

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ID3 Deficiency Alters Chromatin Accessibility at DSB Sites and Enhances Vulnerability to HDAC Inhibition [ATAC-seq]

Project description:The inhibitor of DNA-binding 3 (ID3) plays a crucial role in DNA double-strand break (DSB) repair. We previously reported that ID3 loss reduced chromatin accessibility at DNA repair gene promoters, yet its exact role in DNA repair via chromatin regulation remained elusive. Using the AID-DIvA cell system with inducible DSBs, we show that ID3 directly regulates chromatin accessibility at DSB sites, as demonstrated by reduced chromatin accessibility and lower H3K27ac levels in ID3-knockout (KO) cells. Loss of ID3 renders cells highly sensitive to histone deacetylase (HDAC) inhibition, particularly to the Class I HDAC inhibitor, leading to the accumulation of unrepaired DSBs and delayed cell cycle progression. Transcriptome and proteome analyses revealed that HDAC inhibition in ID3-KO cells results in the downregulation of gene sets involved in the regulation of cell cycle and cell division. The synthetic lethality observed between ID3 loss and Class I HDAC inhibition underscores a novel therapeutic vulnerability in ID3-deficient cancers, driven by compounded defects in chromatin remodeling, cell cycle, and DNA repair. Our study provides new insights into the relationship between chromatin regulation and genome stability, with implications for targeted cancer therapies.

2026-01-29 | GSE301514 | GEO

ID3 Promotes Homologous Recombination via Non-transcriptional and Transcriptional Mechanisms and its Loss Confers Sensitivity to PARP Inhibition

Project description:The inhibitor of DNA-binding 3 (ID3) is a transcriptional regulator that limits interaction of basic helix-loop-helix transcription factors with their target DNA sequences. We previously reported that ID3 loss is associated with mutational signatures linked to DNA repair defects. Here we demonstrate that ID3 exhibits a dual role to promote DNA double-strand break (DSB) repair, particularly homologous recombination (HR). ID3 interacts with the MRN complex and RECQL helicase to activate DSB repair and it facilitates RAD51 loading and downstream steps of HR. In addition, ID3 promotes the expression of HR genes in response to ionizing radiation by regulating both chromatin accessibility and activity of the transcription factor E2F1. Consistently, analyses of TCGA cancer patient data demonstrate that low ID3 expression is associated with impaired HR. The loss of ID3 leads to sensitivity of tumor cells to PARP inhibition, offering new therapeutic opportunities in ID3-deficient tumors.

2022-02-17 | PXD028946 | Pride

ARID1A regulates chromatin organization and establishment of epigenetic marks for DSB repair and transcription silencing

Project description:AT-rich interactive domain-containing protein 1A (ARID1A), a SWI/SNF chromatin remodeling complex subunit, is frequently mutated across various cancer entities. ARID1A contributes to DNA damage response pathways, and we previously reported that ARID1A loss is associated with mutational signatures linked to DNA repair defects. Here we show that ARID1A is promoting both DNA double-strand breaks (DSBs) repair pathways, non-homologous end-joining (NHEJ) and homologous recombination (HR). ARID1A is accumulated at DSBs after DNA damage and regulates the chromatin loop formation at DSB sites by interacting with the cohesin subunit RAD21 and CTCF insulator protein promoting their enrichment around the DSBs. Further analysis demonstrates that ARID1A’s involvement in DSB repair is accompanied by alterations of chromatin accessibility and distribution of activating histone marks at DSBs. ARID1A binds to and promotes the recruitment of the HDAC1 to control transcription repression at these DSBs. Altogether, ARID1A simultaneously regulates DSB repair and transcription silencing in transcriptionally active chromatin. ARID1A depletion resulted in defective DSB repair, which subsequently led to accumulation of micronuclei, activation of cGAS-STING pathway and an increased expression of immunomodulatory cytokines and chemokines upon IR treatment. Furthermore, low ARID1A expression in cancer patients receiving radiotherapy was associated with higher infiltration of several immune cells. The high mutation rate of ARID1A in various cancer types highlights its clinical relevance as a promising biomarker that correlates with the level of immune regulatory cytokines and can estimate the levels of tumor-infiltrating immune cells and response to combination of radio- and immunotherapy.

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ARID1A regulates chromatin organization and establishment of epigenetic marks for DSB repair and transcription silencing

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SCAI promotes DNA double-strand break repair in distinct chromosomal contexts

Project description:DNA double-strand breaks (DSBs) are highly cytotoxic DNA lesions, whose accurate repair by non-homologous end-joining (NHEJ) or homologous recombination (HR) is crucial for genome integrity and is strongly influenced by the local chromatin environment. Here, we identify SCAI (Suppressor of Cancer Cell Invasion) as a 53BP1-interacting chromatin-associated protein that promotes the functionality of several DSB repair pathways in mammalian cells. SCAI undergoes prominent enrichment at DSB sites through dual mechanisms involving 53BP1-dependent recruitment to DSB-surrounding chromatin and 53BP1-independent accumulation at resected DSBs. Cells lacking SCAI display reduced DSB repair capacity, hypersensitivity to DSB-inflicting agents and genome instability. We demonstrate that SCAI is a mediator of 53BP1-dependent repair of heterochromatin-associated DSBs, facilitating ATM kinase signaling at DSBs in repressive chromatin environments. Moreover, we establish an important role of SCAI in meiotic recombination, as SCAI deficiency in mice leads to germ cell loss and subfertility associated with impaired retention of the DMC1 recombinase on meiotic chromosomes. Collectively, our findings uncover SCAI as a physiologically important component of both NHEJ- and HR-mediated pathways that potentiates DSB repair efficiency in specific chromatin contexts.

2016-12-12 | PXD004912 | Pride

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2014-03-23 | E-MTAB-1241 | biostudies-arrayexpress

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Project description:Damage to genomic DNA, especially as DNA double strand breaks (DSB), elicits prompt activation of DNA damage response (DDR) which arrest cell-cycle either G1/S or G2/M to avoid entering S and M phase with DNA damage. In mammalian organs cells are in both proliferating and quiescent states. Quiescent cells are already arrested in G0, therefore there may be fundamental difference in DDR between proliferating and quiescent cells. To address these differences we studied recruitment of DSB repair factors and resolution of DNA lesions induced at site-specific DSBs occurring at different cell cycle phases, i.e. in asynchronously proliferating, G0, and G1 arrested cells. Strikingly, DSBs occurring in G0 quiescent cells are irreparable with a sustained activation of p53-pathway. Conversely, reentry of G0-damaged cells into cell cycle progression, show a delayed clearance of recruited DNA repair factors bound at DSBs, indicating an inefficient repair when compared to DSBs induced in asynchronously proliferating or G1 cells. Moreover, we found that initial recognition of DSBs and assembly of DSB factors is largely similar at different cell cycle phases. Our study thereby demonstrates the crucial role of cell cycle phases in repair and resolution of DSBs.

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Project description:DNA double-strand breaks (DSBs) can be repaired by several pathways. In eukaryotes, repair pathway choice – the cellular decision making underlying DSB repair – occurs at the level of DSB resection and is controlled by the cell cycle. Upon cell cycle-dependent activation, cyclin-dependent kinases (CDKs) phosphorylate resection proteins and thereby stimulate DSB resection and repair by homologous recombination (HR). Here, we identify Dbf4-dependent kinase (DDK) as a second major cell cycle regulator of DNA end resection. Using inducible genetic and chemical inhibition of DDK in budding yeast and human cells, we show that DNA resection and HR require activation by DDK. Mechanistically, DDK catalyzes phosphorylation of at least two resection nucleases. Via phosphorylation of the Mre11 activator Sae2 it promotes activation of resection initiation, via phosphorylation of the Dna2 nuclease it promotes long-range resection. Notably, synthetic activiation of DDK allows limited resection and HR in G1 cells, suggesting that DDK is a key component of DSB repair decision making.

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Project description:The DNA double-strand break (DSB) response is a multi-step process that requires chromatin reorganization at each stage. 53BP1 is a nodal point in this response as it directs chromatin-based DSB repair. However, how chromatin reorganization impacts DSB repair upstream of 53BP1 is not fully understood. Here we reveal that Chromodomain Helicase DNA Binding Protein 7 (CHD7) rapidly recruits to damaged chromatin in a poly(ADP-ribose) polymerase 1 (PARP1)-dependent manner. CHD7 facilitates chromatin relaxation and the loading of canonical non-homologous end-joining (cNHEJ) factors, while restraining 53BP1 accumulation at DSBs. Moreover, CHD7 physically associates with HDAC1/2, thereby recruiting this complex to DNA breaks independently of its chromatin remodeling activity. HDAC1/2 promote histone H4 de-acetylation and chromatin re-compaction to prevent supraphysiological retention of cNHEJ factors at DBSs. Thus, the cooperation between distinct yet coordinated chromatin remodeling activities driven by CHD7 and HDAC1/2 ensures proper assembly dynamics of the cNHEJ machinery and efficient DSB repair.

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Ma2005-digital response of p53 to DNA damage-ATM Activation Module

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