SLF2 in DLBCL
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB47681 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| ERR11417600_1.fastq.gz | Fastqsanger.gz | |||
| ERR11417600_2.fastq.gz | Fastqsanger.gz | |||
| ERR11417601_1.fastq.gz | Fastqsanger.gz | |||
| ERR11417601_2.fastq.gz | Fastqsanger.gz |
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Project description:The DNA damage response (DDR) acts as a barrier to malignant transformation and is often impaired during tumorigenesis. Exploiting the impaired DDR can be a promising therapeutic strategy; however, the mechanisms of inactivation and corresponding biomarkers are incompletely understood. Starting from an unbiased screening approach, we identified the SMC5-SMC6 Complex Localization Factor 2 (SLF2) as a regulator of the DDR and biomarker for a B-cell lymphoma (BCL) patient subgroup with an adverse prognosis. SLF2-deficiency leads to loss of DDR factors including CLSPN and consequently impairs CHK1 activation. In line with this mechanism, genetic deletion of Slf2 drives lymphomagenesis in vivo. Tumor cells lacking SLF2 are characterized by a high level of DNA damage, which leads to alterations of the post-translational SUMOylation pathway as a safeguard. The resulting co-dependency confers synthetic lethality to a clinically applicable SUMOylation inhibitor (SUMOi), and inhibitors of the DDR pathway act highly synergistic with SUMOi. Together, our results identify SLF2 as a DDR regulator and reveal co-targeting of the DDR and SUMOylation as a promising strategy for the treatment of aggressive lymphoma.
2023-07-21 | PXD041851 | Pride
Project description:The DNA damage response (DDR) acts as a barrier to malignant transformation and is often impaired during tumorigenesis. Exploiting the impaired DDR can be a promising therapeutic strategy; however, the mechanisms of inactivation and corresponding biomarkers are incompletely understood. Starting from an unbiased screening approach, we identified the SMC5-SMC6 Complex Localization Factor 2 (SLF2) as a regulator of the DDR and biomarker for a B-cell lymphoma (BCL) patient subgroup with an adverse prognosis. SLF2-deficiency leads to loss of DDR factors including CLSPN and consequently impairs CHK1 activation. In line with this mechanism, genetic deletion of Slf2 drives lymphomagenesis in vivo. Tumor cells lacking SLF2 are characterized by a high level of DNA damage, which leads to alterations of the post-translational SUMOylation pathway as a safeguard. The resulting co-dependency confers synthetic lethality to a clinically applicable SUMOylation inhibitor (SUMOi), and inhibitors of the DDR pathway act highly synergistic with SUMOi. Together, our results identify SLF2 as a DDR regulator and reveal co-targeting of the DDR and SUMOylation as a promising strategy for the treatment of aggressive lymphoma.
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Project description:Homologous recombination-mediated DNA repair deficiency (HRD) predisposes to cancer development, but also provides therapeutic opportunities. Here, we identified an HRD gene signature that robustly predicted HRD status. Unexpectedly, concurrent loss of PTEN in BRCA1-deficient cells might extensively rewire the HR repair network and confer resistance to PARP inhibitor, partially through over-expression of TTK. We used the HRD gene signature as a drug discovery tool and found several PARP-inhibitor-synergizing agents through the connectivity map. Thus gene expression profiling can be used to define the functional status of the HR repair network providing prognostic and therapeutic information. Various shRNAs that target genes involved in homologous recombination (HR) were transfected in MCF-10A non-transformed breast cells lines. Stable HR gene knockdown MCF-10A cells were seeded 200000 at 10 cm plate. Cells were harvested after 48 hours culturing and used for gene expression profiling. The shRNA that target CHK1 gene was transfected in human osteosarcoma U2OS cell line by lentiviral particles and selected stable CHK1 knockdown U2OS cells. Scrambled control shRNA-transfected U2OS cells were applying as control. Both stable CHK1 knockdown and control U2OS cells were seeded with 2 x 10^5 cells at 10 cm culture plate. Cells were cultured in McCOY 5A medium with 10% FBS and harvested after 48 hours culturing. mRNA was extracted from collected cells and performing gene expression profiling. Three biological replicates were applied.
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Project description:The ubiquitin-proteasome system (UPS) plays a crucial role in cellular homeostasis and its major role in genome stability and maintenance is rapidly emerging. Here, we identify the proteasomal shuttle factor ubiquilin-4 (UBQLN4) as a major component of the DNA damage response. We found a homozygous truncating mutation in the UBQLN4 gene in families with a pleiotropic autosomal recessive syndrome with clinical and cellular characteristics of genome instability disorders. UBQLN4 loss leads to cellular hypersensitivity to genotoxic stress and delayed repair of DNA double-strand breaks (DSBs). Furthermore, ATM-dependent phosphorylation of UBQLN4 on S318 is required for cellular protection against DNA damage and proper DSB repair. We demonstrate that UBQLN4 specifically interacts with ubiquitylated MRE11, which mediates early steps of the DSB response. Loss of UBQLN4 leads to retention of MRE11 at DSB sites, which in turn drives a non-physiological initiation of DNA end resection thereby enhancing homologous recombination-mediated DSB repair (HRR). Concomitantly, UBQLN4 depletion is associated with increased HRR activity in vitro and in vivo. In contrast, UBQLN4 over-expression represses HRR and favors DSB repair through non-homologous end joining. Moreover, we find that UBQLN4 is overexpressed in aggressive tumors, including high-risk neuroblastoma. In line with an HRR defect in such tumors, we observe that cell lines derived from these lesions display an actionable PARP1 inhibitor sensitivity. Abnormal UBQLN4 expression thus underlies genome instability-associated morbidity on the one hand and serve as a cancer biomarker on the other hand. Moreover, UBQLN4 may be a promising target for PARP1 inhibition in aggressive cancer.
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Project description:Homologous recombination-mediated DNA repair deficiency (HRD) predisposes to cancer development, but also provides therapeutic opportunities. Here, we identified an HRD gene signature that robustly predicted HRD status. Unexpectedly, concurrent loss of PTEN in BRCA1-deficient cells might extensively rewire the HR repair network and confer resistance to PARP inhibitor, partially through over-expression of TTK. We used the HRD gene signature as a drug discovery tool and found several PARP-inhibitor-synergizing agents through the connectivity map. Thus gene expression profiling can be used to define the functional status of the HR repair network providing prognostic and therapeutic information. Various shRNAs that target genes involved in homologous recombination (HR) were transfected in MCF-10A non-transformed breast cells lines. Stable HR gene knockdown MCF-10A cells were seeded 200000 at 10 cm plate. Cells were harvested after 48 hours culturing and used for gene expression profiling. The shRNAs that target ATM, ATR, CHK1, CHK2, and 53BP1 genes were transfected in MCF-10A non-transformed breast cell line by lentiviral particles and selected stable ATM, ATR, CHK1, CHK2, and 53BP1 knockdown MCF-10A cells. Scrambled control shRNA-transfected and wild type MCF-10A cells were applying as control. All knockdown and control MCF-10A cells were seeded with 2 x 10^5 cells at 10 cm culture plate. Cells were cultured in MCF-10A medium and harvested after 48 hours culturing. mRNA was extracted from collected cells and performing gene expression profiling. Three biological replicates were applied.
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