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NR4A1 suppresses cancer replication stress through R-loop-dependent inhibition of immediate early gene transcriptional elongation

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE161853 | GEO | 2021/11/03

REPOSITORIES: GEO

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NR4A1 suppresses cancer replication stress through R-loop-dependent inhibition of immediate early gene transcriptional elongation [PRO-seq]

Project description:Deregulation of oncogenic proliferative signals triggers replication stress in cancer cells to which they must adapt. Immediate early genes (IEGs), identified by their rapid stress-induced transient bursts of expression, are critical to integrating downstream signaling pathways. In studying tumor initiation by patient-derived breast cancer cells, we observed acquisition of open chromatin domains at the genebody and 3’-UTR of IEGs, uniquely across the genome. Through in vivo and in vitro modeling, we show that the IEG and orphan nuclear receptor NR4A1 localizes across multiple IEG genebodies, where it binds to RNA Pol II, arresting transcriptional elongation and generating extensive R-loops and accessible chromatin. Acute stress promptly removes NR4A1 from IEG genebodies, triggering immediate release of their poised transcripts. In breast cancer cells, NR4A1 overexpression increases tumorigenesis; conversely, its deletion leads to uncompensated replication stress, chromosomal instability and mitotic catastrophe, driven by deregulation of its IEG target FOS. A large fraction of primary breast and other cancers exhibit open genebody chromatin at IEGs, consistent with preserved NR4A1 function. Thus, NR4A1 mediates a novel transcriptional elongation checkpoint, unique to stress-induced genes and required for their rapid bursts of expression. Cancers that have retained this mechanism in adapting to chronic replication stress may be dependent on NR4A1 for proliferation.

2021-11-03 | GSE161780 | GEO

NR4A1 suppresses cancer replication stress through R-loop-dependent inhibition of immediate early gene transcriptional elongation [ChIP-seq]

2021-11-03 | GSE161852 | GEO

NR4A1 suppresses cancer replication stress through R-loop-dependent inhibition of immediate early gene transcriptional elongation [ATAC-seq]

2021-11-03 | GSE161782 | GEO

NR4A1 suppresses cancer replication stress through R-loop-dependent inhibition of immediate early gene transcriptional elongation [DRIP-seq]

2021-11-03 | GSE161781 | GEO

NR4A1 suppresses cancer replication stress through R-loop-dependent inhibition of immediate early gene transcriptional elongation [bulk RNA-seq]

2021-11-03 | GSE161779 | GEO

NR4A1 suppresses cancer replication stress through R-loop-dependent inhibition of immediate early gene transcriptional elongation

Project description:NR4A1 suppresses cancer replication stress through R-loop-dependent inhibition of immediate early gene transcriptional elongation

| PRJNA679620 | ENA

NR4A1 suppresses cancer replication stress through R-loop-dependent inhibition of immediate early gene transcriptional elongation [DRIP-seq]

Project description:NR4A1 suppresses cancer replication stress through R-loop-dependent inhibition of immediate early gene transcriptional elongation [DRIP-seq]

| PRJNA679340 | ENA

NR4A1 suppresses cancer replication stress through R-loop-dependent inhibition of immediate early gene transcriptional elongation [PRO-seq]

Project description:NR4A1 suppresses cancer replication stress through R-loop-dependent inhibition of immediate early gene transcriptional elongation [PRO-seq]

| PRJNA679339 | ENA

NR4A1 suppresses cancer replication stress through R-loop-dependent inhibition of immediate early gene transcriptional elongation [ATAC-seq]

Project description:NR4A1 suppresses cancer replication stress through R-loop-dependent inhibition of immediate early gene transcriptional elongation [ATAC-seq]

| PRJNA679341 | ENA

NR4A1 suppresses cancer replication stress through R-loop-dependent inhibition of immediate early gene transcriptional elongation [ChIP-seq]

Project description:NR4A1 suppresses cancer replication stress through R-loop-dependent inhibition of immediate early gene transcriptional elongation [ChIP-seq]

| PRJNA679622 | ENA

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