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Genome wide analsis of the chromatin accessibility and gene expression in control and NUDT5 depleted U2OS cells [RNA-seq]

ABSTRACT: NUDT5 was reported to generate ATP to support local chromatin remodeling and transcription of hormone-responsive genes. Our research has found that NUDT5 is also required for DNA damage repair by homologous recombination. To investigate how NUDT5 regulates HR, we depleted NUDT5 in U2OS cells by siRNA and compared the transcriptome profiling (RNA-seq) of NUDT5 depleted cells with control cells to investigate whether NUDT5 regulate HR by altering the expression of essential components of the HR machinery. The results suggest that NUDT5 does not regulate HR by altering the expression of essential components of the HR machinery. To investigate whether NUDT5 contributes to chromatin remodeling after DNA damage, we compared the chromatin accessibility profiling (ATAC-seq) in NUDT5 depleted U2OS cells and control cells, either before or after ionizing radiation. The results suggest that NUDT5 silencing blocked most DNA damage-induced changes in chromatin accessibility following radiation exposure and implies that NUDT5 may support the activity of remodeling ATPases during damage repair.

ORGANISM(S): Homo sapiens

PROVIDER: GSE196722 | GEO | 2023/02/14

REPOSITORIES: GEO

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Project description:DNA damage activates a complex signaling network in cells that blocks cell cycle progression, recruits factors involved in DNA repair, and/or triggers programs that control senescence or programmed cell death. Alterations in chromatin structure are known to be important for the initiation and propagation of the DNA damage response, although the molecular details are unclear. We investigated the role of chromatin structure in the DNA damage response by monitoring multiple timedependent checkpoint signaling and response events with a high-content multiplex image-based RNAi screen of chromatin modifying and interacting genes. We discovered that Brd4, a double bromodomain-containing protein, functions as an endogenous inhibitor of DNA damage signaling by binding to acetylated histones at sites of open chromatin and altering chromatin accessibility. Loss of Brd4 or disruption of acetyl-lysine binding results in an increase in both the number and size of radiation-induced !H2AX nuclear foci while overexpression of a Brd4 splice isoform completely suppresses !H2AX formation, despite equivalent double strand break formation. Brd4 knock-down cells displayed altered chromatin structure, prolonged cell cycle checkpoint arrest and enhanced survival after irradiation, while overexpression of Brd4 isoform B results in enhanced radiationinduced lethality. Brd4 is the target of the t(15;19) chromosomal translocation in a rare form of cancer, NUT Midline Carcinoma. Acetyl lysine-bromodomain interactions of the Brd4-NUT fusion protein suppresses !H2AX foci in discrete nuclear compartments, rendering cells more radiosensitive, mimicking overexpression of Brd4 isoform B. NUT Midline Carcinoma is sensitive to radiotherapy, however tumor material from this rare cancer is scarce. We therefore investigated Brd4 expression in another human cancer commonly treated with radiotherapy, glioblastoma multiforme, and found that expression of Brd4 isoform B correlated specifically with treatment response to radiotherapy. These data implicate Brd4 as an endogenous insulator of DNA damage signaling through recognition of epigenetic modifications in chromatin and suggest that expression of the Brd4 in human cancer can modulate the clinical response to DNA-damaging cancer therapy. Two replicates each of U2OS cells expressing either Brd4 shRNA or a control shRNA

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Genome wide analsis of the chromatin accessibility and gene expression in control and NUDT5 depleted U2OS cells [RNA-seq]

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