Molecular underpinnings and environmental drivers of loss of heterozygosity in Drosophila intestinal stem cells
Summary: During development and aging, genome mutation leading to loss of heterozygosity (LOH) can uncover recessive phenotypes within tissue compartments. This phenomenon occurs in normal human tissues and is prevalent in pathological genetic conditions and cancers. While studies in yeast have defi...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-12-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723014973 |
| _version_ | 1797448075538595840 |
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| author | Lara Al Zouabi Marine Stefanutti Spyridon Roumeliotis Gwenn Le Meur Benjamin Boumard Nick Riddiford Natalia Rubanova Mylène Bohec Louis Gervais Nicolas Servant Allison J. Bardin |
| author_facet | Lara Al Zouabi Marine Stefanutti Spyridon Roumeliotis Gwenn Le Meur Benjamin Boumard Nick Riddiford Natalia Rubanova Mylène Bohec Louis Gervais Nicolas Servant Allison J. Bardin |
| author_sort | Lara Al Zouabi |
| collection | DOAJ |
| description | Summary: During development and aging, genome mutation leading to loss of heterozygosity (LOH) can uncover recessive phenotypes within tissue compartments. This phenomenon occurs in normal human tissues and is prevalent in pathological genetic conditions and cancers. While studies in yeast have defined DNA repair mechanisms that can promote LOH, the predominant pathways and environmental triggers in somatic tissues of multicellular organisms are not well understood. Here, we investigate mechanisms underlying LOH in intestinal stem cells in Drosophila. Infection with the pathogenic bacteria, Erwinia carotovora carotovora 15, but not Pseudomonas entomophila, increases LOH frequency. Using whole genome sequencing of somatic LOH events, we demonstrate that they arise primarily via mitotic recombination. Molecular features and genetic evidence argue against a break-induced replication mechanism and instead support cross-over via double Holliday junction-based repair. This study provides a mechanistic understanding of mitotic recombination, an important mediator of LOH, and its effects on stem cells in vivo. |
| first_indexed | 2024-03-09T14:05:08Z |
| format | Article |
| id | doaj.art-bc7cd3a3c8c7477faf2b30300a471dba |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-03-09T14:05:08Z |
| publishDate | 2023-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-bc7cd3a3c8c7477faf2b30300a471dba2023-11-30T05:07:19ZengElsevierCell Reports2211-12472023-12-014212113485Molecular underpinnings and environmental drivers of loss of heterozygosity in Drosophila intestinal stem cellsLara Al Zouabi0Marine Stefanutti1Spyridon Roumeliotis2Gwenn Le Meur3Benjamin Boumard4Nick Riddiford5Natalia Rubanova6Mylène Bohec7Louis Gervais8Nicolas Servant9Allison J. Bardin10Genetics and Developmental Biology Department, Institut Curie, PSL Research University, Sorbonne University, CNRS UMR 3215, INSERM U934, 75248 Paris, FranceGenetics and Developmental Biology Department, Institut Curie, PSL Research University, Sorbonne University, CNRS UMR 3215, INSERM U934, 75248 Paris, FranceGenetics and Developmental Biology Department, Institut Curie, PSL Research University, Sorbonne University, CNRS UMR 3215, INSERM U934, 75248 Paris, FranceGenetics and Developmental Biology Department, Institut Curie, PSL Research University, Sorbonne University, CNRS UMR 3215, INSERM U934, 75248 Paris, FranceGenetics and Developmental Biology Department, Institut Curie, PSL Research University, Sorbonne University, CNRS UMR 3215, INSERM U934, 75248 Paris, FranceGenetics and Developmental Biology Department, Institut Curie, PSL Research University, Sorbonne University, CNRS UMR 3215, INSERM U934, 75248 Paris, FranceGenetics and Developmental Biology Department, Institut Curie, PSL Research University, Sorbonne University, CNRS UMR 3215, INSERM U934, 75248 Paris, France; Bioinformatics, Biostatistics, Epidemiology and Computational Systems Unit, Institut Curie, PSL Research University, INSERM U900, 75005 Paris, FranceICGex Next-Generation Sequencing Platform, Institut Curie, PSL Research University, 75005 Paris, FranceGenetics and Developmental Biology Department, Institut Curie, PSL Research University, Sorbonne University, CNRS UMR 3215, INSERM U934, 75248 Paris, FranceBioinformatics, Biostatistics, Epidemiology and Computational Systems Unit, Institut Curie, PSL Research University, INSERM U900, 75005 Paris, FranceGenetics and Developmental Biology Department, Institut Curie, PSL Research University, Sorbonne University, CNRS UMR 3215, INSERM U934, 75248 Paris, France; Corresponding authorSummary: During development and aging, genome mutation leading to loss of heterozygosity (LOH) can uncover recessive phenotypes within tissue compartments. This phenomenon occurs in normal human tissues and is prevalent in pathological genetic conditions and cancers. While studies in yeast have defined DNA repair mechanisms that can promote LOH, the predominant pathways and environmental triggers in somatic tissues of multicellular organisms are not well understood. Here, we investigate mechanisms underlying LOH in intestinal stem cells in Drosophila. Infection with the pathogenic bacteria, Erwinia carotovora carotovora 15, but not Pseudomonas entomophila, increases LOH frequency. Using whole genome sequencing of somatic LOH events, we demonstrate that they arise primarily via mitotic recombination. Molecular features and genetic evidence argue against a break-induced replication mechanism and instead support cross-over via double Holliday junction-based repair. This study provides a mechanistic understanding of mitotic recombination, an important mediator of LOH, and its effects on stem cells in vivo.http://www.sciencedirect.com/science/article/pii/S2211124723014973CP: Developmental biologyCP: Genomics |
| spellingShingle | Lara Al Zouabi Marine Stefanutti Spyridon Roumeliotis Gwenn Le Meur Benjamin Boumard Nick Riddiford Natalia Rubanova Mylène Bohec Louis Gervais Nicolas Servant Allison J. Bardin Molecular underpinnings and environmental drivers of loss of heterozygosity in Drosophila intestinal stem cells Cell Reports CP: Developmental biology CP: Genomics |
| title | Molecular underpinnings and environmental drivers of loss of heterozygosity in Drosophila intestinal stem cells |
| title_full | Molecular underpinnings and environmental drivers of loss of heterozygosity in Drosophila intestinal stem cells |
| title_fullStr | Molecular underpinnings and environmental drivers of loss of heterozygosity in Drosophila intestinal stem cells |
| title_full_unstemmed | Molecular underpinnings and environmental drivers of loss of heterozygosity in Drosophila intestinal stem cells |
| title_short | Molecular underpinnings and environmental drivers of loss of heterozygosity in Drosophila intestinal stem cells |
| title_sort | molecular underpinnings and environmental drivers of loss of heterozygosity in drosophila intestinal stem cells |
| topic | CP: Developmental biology CP: Genomics |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723014973 |
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