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DNA polymerase ε harmonizes topological states and R-loops formation to maintain genome integrity in Arabidopsis

ABSTRACT: DNA polymerase ε harmonizes topological states and R-loops formation to maintain genome integrity in Arabidopsis

PROVIDER: PRJNA892489 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25153324_1.fastq.gz	Fastqsanger.gz
	SRR25153324_2.fastq.gz	Fastqsanger.gz
	SRR25153325_1.fastq.gz	Fastqsanger.gz
	SRR25153325_2.fastq.gz	Fastqsanger.gz
	SRR25153326_1.fastq.gz	Fastqsanger.gz

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DNA polymerase ε harmonizes topological states and R-loops formation to maintain genome integrity in Arabidopsis

Project description:Genome topology is tied to R-loop formation and genome stability. However, the regulatory mechanism remains to be elucidated. By establishing a system to sense the connections between R-loops and genome topology states, we show that inhibiting DNA topoisomerase 1 (TOP1i) triggers the global increase of R-loops (called topoR-loops) and DNA damages, which are exacerbated in the DNA damage repair-compromised mutant atm. Further suppressor screen identifies a mutation in POL2A, the catalytic subunit of DNA polymerase ?, liberating the TOP1i-induced topoR-loop accumulation and genome instability in atm. Additionally, we find a highly conserved junction domain between the exonuclease and polymerase domains in POL2A that is required for modulating topoR-loops near DNA replication origins and facilitating faithful DNA replication. Our results suggest that DNA replication is in concert with genome topological states to fine-tune R-loops and thereby maintain genome integrity, revealing a presumably conserved regulatory mechanism of TOP1i resistance in chemotherapy for ATM-deficient cancers.

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DNA polymerase ε harmonizes topological states and R-loops formation to maintain genome integrity in Arabidopsis.

Project description:Genome topology is tied to R-loop formation and genome stability. However, the regulatory mechanism remains to be elucidated. By establishing a system to sense the connections between R-loops and genome topology states, we show that inhibiting DNA topoisomerase 1 (TOP1i) triggers the global increase of R-loops (called topoR-loops) and DNA damages, which are exacerbated in the DNA damage repair-compromised mutant atm. A suppressor screen identifies a mutation in POL2A, the catalytic subunit of DNA polymerase ε, rescuing the TOP1i-induced topoR-loop accumulation and genome instability in atm. Importantly we find that a highly conserved junction domain between the exonuclease and polymerase domains in POL2A is required for modulating topoR-loops near DNA replication origins and facilitating faithful DNA replication. Our results suggest that DNA replication acts in concert with genome topological states to fine-tune R-loops and thereby maintain genome integrity, revealing a likely conserved regulatory mechanism of TOP1i resistance in chemotherapy for ATM-deficient cancers.

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

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

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PSIP1/LEDGF reduces R-loops at transcription sites and maintain genome integrity (HEK293T CUT&Tag-Seq)

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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.

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