SLFN11 blocks stressed replication forks independently of ATR
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA394710 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5831760_1.fastq.gz | Fastqsanger.gz | |||
| SRR5831760_2.fastq.gz | Fastqsanger.gz | |||
| SRR5831921_1.fastq.gz | Fastqsanger.gz | |||
| SRR5831921_2.fastq.gz | Fastqsanger.gz | |||
| SRR5831922_1.fastq.gz | Fastqsanger.gz |
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Project description:SLFN11 sensitizes cancer cells to a broad range of DNA-targeted therapies. Here we show that, in response to replication stress induced by camptothecin, SLFN11 tightly binds chromatin at stressed replication foci via RPA1 together with the replication helicase subunit MCM3. Unlike ATR, SLFN11 neither interferes with the loading of CDC45 and PCNA nor inhibits the initiation of DNA replication but selectively blocks fork progression while inducing chromatin opening across replication initiation sites. The ATPase domain of SLFN11 is required for chromatin opening, replication block and cell death but not for the tight binding of SLFN11 to chromatin. Replication stress by the CHK1 inhibitor Prexasertib also recruits SLFN11 to nascent replicating DNA together with CDC45 and PCNA. We conclude that SLFN11 is recruited to stressed replication forks carrying extended RPA filaments where it blocks replication by changing chromatin structure across replication sites.
2018-01-18 | GSE101516 | GEO
Project description:SLFN11 sensitizes cancer cells to a broad range of DNA-targeted therapies. Here we show that, in response to replication stress induced by camptothecin, SLFN11 tightly binds chromatin at stressed replication foci via RPA1 together with the replication helicase subunit MCM3. Unlike ATR, SLFN11 neither interferes with the loading of CDC45 and PCNA nor inhibits the initiation of DNA replication but selectively blocks fork progression while inducing chromatin opening across replication initiation sites. The ATPase domain of SLFN11 is required for chromatin opening, replication block and cell death but not for the tight binding of SLFN11 to chromatin. Replication stress by the CHK1 inhibitor Prexasertib also recruits SLFN11 to nascent replicating DNA together with CDC45 and PCNA. We conclude that SLFN11 is recruited to stressed replication forks carrying extended RPA filaments where it blocks replication by changing chromatin structure across replication sites.
2018-01-18 | GSE101512 | GEO
Project description:SLFN11 sensitizes cancer cells to a broad range of DNA-targeted therapies. Here we show that, in response to replication stress induced by camptothecin, SLFN11 tightly binds chromatin at stressed replication foci via RPA1 together with the replication helicase subunit MCM3. Unlike ATR, SLFN11 neither interferes with the loading of CDC45 and PCNA nor inhibits the initiation of DNA replication but selectively blocks fork progression while inducing chromatin opening across replication initiation sites. The ATPase domain of SLFN11 is required for chromatin opening, replication block and cell death but not for the tight binding of SLFN11 to chromatin. Replication stress by the CHK1 inhibitor Prexasertib also recruits SLFN11 to nascent replicating DNA together with CDC45 and PCNA. We conclude that SLFN11 is recruited to stressed replication forks carrying extended RPA filaments where it blocks replication by changing chromatin structure across replication sites.
2018-01-18 | GSE101515 | GEO
Project description:SLFN11 sensitizes cancer cells to a broad range of DNA-targeted therapies. Here we show that, in response to replication stress induced by camptothecin, SLFN11 tightly binds chromatin at stressed replication foci via RPA1 together with the replication helicase subunit MCM3. Unlike ATR, SLFN11 neither interferes with the loading of CDC45 and PCNA nor inhibits the initiation of DNA replication but selectively blocks fork progression while inducing chromatin opening across replication initiation sites. The ATPase domain of SLFN11 is required for chromatin opening, replication block, and cell death but not for the tight binding of SLFN11 to chromatin. Replication stress by the CHK1 inhibitor Prexasertib also recruits SLFN11 to nascent replicating DNA together with CDC45 and PCNA. We conclude that SLFN11 is recruited to stressed replication forks carrying extended RPA filaments where it blocks replication by changing chromatin structure across replication sites.
| S-EPMC5802881 | biostudies-literature
Project description:SLFN11 blocks stressed replication forks independently of ATR
| PRJNA394713 | ENA
Project description:SLFN11 blocks stressed replication forks independently of ATR (NS-Seq)
| PRJNA394712 | ENA
Project description:Large independent analyses on cancer cell lines followed by functional studies have identified Schlafen 11 (SLFN11), a putative helicase, as the strongest predictor of sensitivity to DNA-damaging agents (DDA), including platinum. However, its role as a prognostic biomarker is undefined, partially due to the lack of validated methods to score SLFN11 in human tissues. Here, we implemented a pipeline to quantify SLFN11 in human cancer samples. By analyzing a cohort of high-grade serous ovarian carcinoma (HGSOC) specimens prior platinum-based chemotherapy treatment, we show, for the first time, that SLFN11 density in both the neoplastic and microenvironmental components was independently associated with favorable outcome. We observed SLFN11 expression in both infiltrating innate and adaptive immune cells, and analyses in a second, independent, cohort revealed that SLFN11 is associated with immune activation in HGSOC. We found that platinum treatments activated immune-related pathways in ovarian cancer cells in a SLFN11-dependent manner, representative of tumor-immune transactivation. Moreover, SLFN11 expression was induced in activated, isolated, immune cell subpopulations, hinting that SLFN11 in the immune compartment may be an indicator of immune transactivation. In summary, we propose SLFN11 is a dual biomarker capturing simultaneously interconnected immunological and cancer-cell-intrinsic functional dispositions associated with sensitivity to DDA treatment.
2021-07-13 | GSE179896 | GEO
Project description:Unscheduled R-loops are a major source of replication stress and DNA damage. R-loop-induced replication defects are sensed and suppressed by ATR kinase, whereas it is not known whether R-loop itself is actively involved in ATR activation and, if so, how this is achieved. Here, we report that the nuclear form of RNA-editing enzyme ADAR1 promotes ATR activation and resolves genome-wide R-loops, a process that requires its double-stranded RNA-binding domains. Mechanistically, ADAR1 interacts with TOPBP1 and facilitates its loading on perturbed replication forks by enhancing the association of TOPBP1 with RAD9 of the 9-1-1 complex. When replication is inhibited, DNA-RNA hybrid competes with TOPBP1 for ADAR1 binding to promote the translocation of ADAR1 from damaged fork to R-loop region. There, ADAR1 recruits RNA helicases DHX9 and DDX21 to unwind R-loops, simultaneously allowing TOPBP1 to stimulate ATR more efficiently. Collectively, we propose that the tempo-spatially regulated assembly of ADAR1-nucleated protein complexes link R-loop clearance and ATR activation, while R-loops crosstalk with blocked replication forks by transposing ADAR1 to finetune ATR activity and safeguard the genome.
2023-09-01 | GSE217878 | GEO
Project description:Schlafen 11 (SLFN11) has recently arisen as a novel cellular restriction factor against replication stress. Here we show that SLFN11 increases chromatin accessibility genome-wide, dominantly at promoters in response to replication stress induced by the CHK1 inhibitor prexasertib and the topoisomerase I inhibitor, camptothecin. Concomitantly SLFN11 selectively activates cellular stress response pathways by inducing the transcription of the Immediate Early Genes (IEGs) including JUN, FOS, EGR1, NFKB2 and ATF3. Both chromatin opening and IEG activation require the putative helicase activity of SLFN11 whereas extrinsic IEG activation by serum induction is SLFN11-independent. SLFN11-dependent IEG activation is also observed across 55 non-isogenic NCI-60 cell lines by comparing transcriptome data before and after camptothecin treatment. We conclude that SLFN11 acts as a global regulator of chromatin structure and an intrinsic IEG activator with the potential to engage the native immune activation in response to replicative stress.
2020-01-17 | GSE140175 | GEO
Project description:Schlafen 11 (SLFN11) has recently arisen as a novel cellular restriction factor against replication stress. Here we show that SLFN11 increases chromatin accessibility genome-wide, dominantly at promoters in response to replication stress induced by the CHK1 inhibitor prexasertib and the topoisomerase I inhibitor, camptothecin. Concomitantly SLFN11 selectively activates cellular stress response pathways by inducing the transcription of the Immediate Early Genes (IEGs) including JUN, FOS, EGR1, NFKB2 and ATF3. Both chromatin opening and IEG activation require the putative helicase activity of SLFN11 whereas extrinsic IEG activation by serum induction is SLFN11-independent. SLFN11-dependent IEG activation is also observed across 55 non-isogenic NCI-60 cell lines by comparing transcriptome data before and after camptothecin treatment. We conclude that SLFN11 acts as a global regulator of chromatin structure and an intrinsic IEG activator with the potential to engage the native immune activation in response to replicative stress.
2020-01-17 | GSE140937 | GEO