Biology subjects

Monin, J.

Publications and source records attributed to Monin, J..

3 recordsLinked to original sources

bioRxiv2025

The Breakome of BRCA1 and BRCA2 Pathway Mutation Carriers Reveals Early Processes in Breast Oncogenesis

DNA double-strand breaks (DSBs) can lead to genomic instability in cancer. Cells rely on an efficient DNA damage response (DDR) to maintain their DNA integrity and prevent oncogenic transformation. However, the early events that connect recurrent DNA damage to oncogenesis are not yet fully understood. Here, using next generation sequencing we comprehensively surveyed genomes to identify DSBs in primary cells of non-malignant carriers of BRCA1 and BRCA2 mutations (BRCAmut), categorized as high-risk patients, to characterize the effects of homologous recombination (HR) loss on cancer initiation. We demonstrate that the landscape of physiological DSBs in BRCAmut mammary epithelial cells differs from that of healthy controls and resemble more the DSB pattern observed in breast cancer cells. Our results reveal that proto-oncogenes and tumor suppressors contain more breaks in BRCAmut samples, and that genes with a high number of DSBs tend to be more highly expressed. These genes containing a high number of DSBs are also often mutated in breast cancer tumors. Finally, genes with high DSBs in mammary epithelial cells from women with BRCAmut exhibit a strong correlation with homologous recombination repair. Together, our findings underscore the impact of BRCA loss on the early stages of carcinogenesis and highlight future possibilities for early cancer detection. Graphical abstractWhen BRCA is intact, genes that are highly broken are properly repaired via HR, preserving DNA integrity. When BRCA is mutant, impairing its function, highly broken transcriptional DSB genes emerge, no longer able to be efficiently repaired via HR, and are found at genes related to cancer signaling. Breakome of enriched breaks at high-risk model resembles breast cancer breakome, and breaks can be found in genes known to be frequently mutated in breast cancer.

cancer biology↗

bioRxiv2025

The landscape and consequences of transcription stress

Cancer is characterized by uncontrolled proliferation accompanied by the hypertranscription of oncogenes, leading to transcription stress, a key source of DNA double-strand breaks (DSBs) that jeopardize genomic stability. Yet, transcription stress is still underexplored. In this study, we utilized maps of DSBs identified through in-suspension break labeling in situ and sequencing (sBLISS), along with transcription stress markers, revealing that transcription stress regions coincide with the super-enhancer regulatory landscape. Notably, {gamma}H2AX mapping indicates its enrichment at transcription stress sites, while not all DSB-enriched genes show equal {gamma}H2AX marking, but those with DSBs tied to transcription stress are distinctly marked. Intriguingly, genes with high-DSBs marked by {gamma}H2AX exhibited significantly higher DSB turnover and repair than those with {gamma}H2AX-low genes, manifesting vulnerability to mutagenesis. These findings underscore super-enhancer activity as a determinant of the transcription stress landscape in cancer, posing a threat to the genomic stability of oncogenes.

molecular biology↗

bioRxiv2023

Mesenchymal stem cell models reveal critical role of Myc as early molecular event in osteosarcomagenesis

Osteosarcoma is an aggressive bone tumor that primarily affects children and adolescents. This malignancy is highly aggressive, associated with poor clinical outcomes, and primarily metastasizes to the lungs. Due to its rarity and biological heterogeneity, limited studies on its molecular basis exist, hindering the development of effective therapies. The WW domain-containing oxidoreductase (WWOX) is frequently altered in human osteosarcoma. Combined deletion of Wwox and Trp53 using Osterix1-Cre transgenic mice has been shown to accelerate osteosarcoma development. In this study, we generated a traceable osteosarcoma mouse model harboring the deletion of Trp53 alone (single-knockout) or combined deletion of Wwox/Trp53 (double-knockout) and expressing a tdTomato reporter. By tracking Tomato expression at different time points, we detected the early presence of tdTomato-positive cells in the bone marrow mesenchymal stem cells of non-osteosarcoma-bearing mice (young BM). We found that double-knockout young BM cells, but not single-knockout young BM cells, exhibited tumorigenic traits both in vitro and in vivo. Molecular and cellular characterization of these double-knockout young BM cells revealed their resemblance to osteosarcoma tumor cells. Interestingly, one of the observed significant transcriptomic changes in double-knockout young BM cells was the upregulation of Myc and its target genes compared to single-knockout young BM cells. Intriguingly, Myc-chromatin immunoprecipitation sequencing revealed its increased enrichment on Myc targets, which were upregulated in double-knockout young BM cells. Restoration of WWOX in double-knockout young BM cells reduced Myc protein levels. As a prototype target, we demonstrated the upregulation of MCM7, a known Myc target, in double-knockout young BM relative to single-knockout young BM cells. Inhibition of MCM7 expression using simvastatin resulted in reduced proliferation and tumor cell growth of double-knockout young BM cells. Our findings reveal BM mesenchymal stem cells as a platform to study osteosarcoma and Myc and its targets as WWOX effectors and early molecular events during osteosarcomagenesis.

cancer biology↗