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PSIP1/LEDGF reduces R-loops at transcription sites and maintain genome integrity

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

ORGANISM(S): Homo sapiens

PROVIDER: GSE220234 | GEO | 2023/12/08

REPOSITORIES: GEO

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PSIP1/LEDGF reduces R-loops at transcription sites to maintain genome integrity.

Project description:R-loops that accumulate at transcription sites pose a persistent threat to genome integrity. PSIP1 is a chromatin protein associated with transcriptional elongation complex, possesses histone chaperone activity, and is implicated in recruiting RNA processing and DNA repair factors to transcription sites. Here, we show that PSIP1 interacts with R-loops and other proteins involved in R-loop homeostasis, including PARP1. Genome-wide mapping of PSIP1, R-loops and γ-H2AX in PSIP1-depleted human and mouse cell lines revealed an accumulation of R-loops and DNA damage at gene promoters in the absence of PSIP1. R-loop accumulation causes local transcriptional arrest and transcription-replication conflict, leading to DNA damage. PSIP1 depletion increases 53BP1 foci and reduces RAD51 foci, suggesting altered DNA repair choice. Furthermore, PSIP1 depletion increases the sensitivity of cancer cells to PARP1 inhibitors and DNA-damaging agents that induce R-loop-induced DNA damage. These findings provide insights into the mechanism through which PSIP1 maintains genome integrity at the site of transcription.

| S-EPMC10774266 | biostudies-literature

PSIP1/LEDGF reduces R-loops at transcription sites and maintain genome integrity (TT-Seq)

Project description:R-loops are transcriptional by-products that pose a persistent threat to genome integrity and are implicated in accelerated ageing and cancer. PSIP1/LEDGF is a multifunctional chromatin protein that associates with transcriptional elongation machinery. Here, we demonstrated that PSIP1 interacts with R-loops generated at the site of transcription and along with the factors involved in R-loop resolution, including PARP1. Reduced PSIP1 levels in human and mouse cells lead to an increase in R-loop levels and DNA damage at the PSIP1 binding sites. This increased R-loops and DNA damage was specific at the RNA polymerase II transcription sites, causing local transcriptional arrest. In addition, we demonstrate that PSIP1 can be targeted for increasing the sensitivity of cancer cells to PARP1 inhibitors and transcription-coupled DNA damaging agents. These findings show the critical role of PSIP1 in reducing the R-loop burden and DNA damage at the transcriptionally active regions of the genome.

2023-12-08 | GSE220233 | GEO

PSIP1/LEDGF reduces R-loops at transcription sites and maintain genome integrity (RNA-Seq)

2023-12-08 | GSE220232 | GEO