Project description:This study characterizes the genomic and immunophenotypic landscape of pancreatic ductal adenocarcinoma in carriers of germline pathogenic variants in ATM to improve our understanding of the mechanistic pathways involved in pancreas cancer development in germline ATM carriers and aid in the identification of targeted therapeutic strategies.
Project description:The ataxia telangiectasia-mutated (ATM) gene is a moderate-risk breast cancer susceptibility gene; germline loss-of-function variants are found in up to 3% of hereditary breast and ovarian cancer (HBOC) families who undergo genetic testing. So far, no clear molecular features of breast tumors occuring in ATM deleterious variant carriers have been described, but identification of an ATM-associated tumors signature may help patients' management. To characterize hallmarks of ATM-associated tumors, absolute copy number variation and loss of heterozygosity profiles were obtained from the OncoScan SNP array.
Project description:Germline telomere maintenance defects provoke inflammatory disease via activated ATM/YAP1/IL-18 signaling in epithelial cells, providing novel therapies for inflammatory conditions associated with short telomeres.
Project description:Genomic integrity within transcriptionally active regions is crucial for averting oncogenic mutations, yet the precise mechanisms governing DNA double-strand break (DSB) repair in these areas remain elusive. This study reveals that the IRAK1-spliceosome axis orchestrates small nuclear RNA (snRNA) as a central molecular hub, potently activating the ATM at DSB sites within active chromatin to enable precise repair. Mechanistically, IRAK1 phosphorylates spliceosomal SR proteins to recruit snRNA to DSBs, inducing condensation of the MRN complex near transcriptionally active regions to create an ATM activation platform. Inhibition of the IRAK1-spliceosome-snRNA axis compromises ATM activation at damaged sites in active regions, leading to increased mutations exclusively within these regions and heightened sensitivity to etoposide—a drug targeting active chromatin. In summary, we have elucidated that snRNA functions as a pivotal transcription-repair bridge, connecting transcriptional processes via spliceosomes to ATM-dependent repair mechanisms to promote accurate repair within transcriptionally active chromatin.
Project description:Genomic integrity within transcriptionally active regions is crucial for averting oncogenic mutations, yet the precise mechanisms governing DNA double-strand break (DSB) repair in these areas remain elusive. This study reveals that the IRAK1-spliceosome axis orchestrates small nuclear RNA (snRNA) as a central molecular hub, potently activating the ATM at DSB sites within active chromatin to enable precise repair. Mechanistically, IRAK1 phosphorylates spliceosomal SR proteins to recruit snRNA to DSBs, inducing condensation of the MRN complex near transcriptionally active regions to create an ATM activation platform. Inhibition of the IRAK1-spliceosome-snRNA axis compromises ATM activation at damaged sites in active regions, leading to increased mutations exclusively within these regions and heightened sensitivity to etoposide—a drug targeting active chromatin. In summary, we have elucidated that snRNA functions as a pivotal transcription-repair bridge, connecting transcriptional processes via spliceosomes to ATM-dependent repair mechanisms to promote accurate repair within transcriptionally active chromatin.
Project description:Genomic integrity within transcriptionally active regions is crucial for averting oncogenic mutations, yet the precise mechanisms governing DNA double-strand break (DSB) repair in these areas remain elusive. This study reveals that the IRAK1-spliceosome axis orchestrates small nuclear RNA (snRNA) as a central molecular hub, potently activating the ATM at DSB sites within active chromatin to enable precise repair. Mechanistically, IRAK1 phosphorylates spliceosomal SR proteins to recruit snRNA to DSBs, inducing condensation of the MRN complex near transcriptionally active regions to create an ATM activation platform. Inhibition of the IRAK1-spliceosome-snRNA axis compromises ATM activation at damaged sites in active regions, leading to increased mutations exclusively within these regions and heightened sensitivity to etoposide—a drug targeting active chromatin. In summary, we have elucidated that snRNA functions as a pivotal transcription-repair bridge, connecting transcriptional processes via spliceosomes to ATM-dependent repair mechanisms to promote accurate repair within transcriptionally active chromatin.
Project description:Pancreatic ductal adenocarcinoma (PDAC) is associated with accumulation of particular oncogenic mutations and recent genetic sequencing studies have identified ataxia telangiectasia-mutated (ATM) mutations in PDAC cohorts. Here we report that conditional deletion of ATM in a mouse model of PDAC induces a greater number of proliferative precursor lesions coupled with a pronounced fibrotic reaction. ATM-targeted mice display altered TGFβ-superfamily signalling and enhanced epithelial-to-mesenchymal transition (EMT) coupled with shortened survival. Notably, our mouse model recapitulates many features of more aggressive human PDAC subtypes. Particularly, we report that low expression of ATM predicts EMT, a gene signature specific for Bmp4 signalling and poor prognosis in human PDAC. Our data suggest an intimate link between ATM expression and pancreatic cancer progression in mice and men. KC (Atm+/+) and AKC (Atm-/-) mouse pancreata at 5 weeks old (n= 3 KC; n= 3 AKC) or 10 weeks old (n=3 KC; n=4 AKC) were subjected to microarray analysis.