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Mechanisms of spontaneous loss of heterozygosity in adult stem cells

Abstract : Sometimes a somatic cell undergoes an alteration of its genome leading to loss of heterozygosity (LOH). This phenomenon occurs in normal human tissues, pathological disorders, and cancers. Although previous studies in yeast have provided substantial insight into different mechanisms of LOH, mechanistic details are lacking in higher eukaryotes. Here we investigated the mechanisms giving rise to LOH, bridging the gap between unicellular yeast and higher eukaryotes using an in vivo stem cell model system in Drosophila. Our previous studies have shown that LOH arises frequently in Drosophila intestinal stem cells, and that spontaneous neoplasia arise due to LOH of tumour suppressor genes (Siudeja, 2015). Though whole-genome sequencing of somatic LOH events and profiling copy number changes and changes in heterozygosity of single-nucleotide polymorphisms, we demonstrated that LOH arises through mitotic recombination. Consistent with this, we found Rad51 to be implicated in LOH. Fine mapping of recombination sites did not reveal mutational pile-ups that commonly arise with a break-induced replication mechanism and instead showed clear examples of chromosomes resulting from cross-over resulting from double-Holliday junction-based repair. The mapped recombination regions also provided insight into potential genomic sequence features that may promote mitotic recombination, including an association with the repeated region of the Histone Locus Cluster and regions previously mapped to form R loops. We further explored how environmental factors can influence this process and demonstrate that infection with the enteric pathogenic bacteria, Ecc15, increased LOH frequency. This study provides a better mechanistic understanding of how mitotic recombination arises in stem cells in vivo, and identifies intrinsic and extrinsic factors that can drive LOH, thus providing important insight into cancer initiation and potential preventative and therapeutic strategies.
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Submitted on : Friday, March 4, 2022 - 3:50:08 PM
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  • HAL Id : tel-03598037, version 1


Lara Al-Zoubi. Mechanisms of spontaneous loss of heterozygosity in adult stem cells. Cellular Biology. Université Paris sciences et lettres, 2020. English. ⟨NNT : 2020UPSLT017⟩. ⟨tel-03598037⟩



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