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Updated: Jun 30, 2026
In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila
Published on: August 20, 2019
Mutation of the gene encoding the ubiquitin activating enzyme ubal causes tissue overgrowth in Drosophila
Cathie M Pfleger1, Kieran F Harvey, Hua Yan
1Massachusetts General Hospital Canter Center, Massachusetts General Hospital, Chrlestown, Massachusetts, USA.
Abstract:
Protein ubiquitination has been shown to regulate a wide variety of cellular process including cell cycle progression, protein trafficking and apoptosis. Most regulation of ubiquitination occurs at the level of E2 or E3 enzymes and their interactions with specific substrates. In a screen for mutations that cause tissue overgrowth, we recovered multiple mutations in the Drosophila Uba1 gene that encodes the E1 enzyme that is required for the first step of most, if not all, ubiquitination reactions. Previous studies with yeast and mammalian cells have shown that disrupting E1 function results in a cell-cycle arrest. Here we show that in the developing Drosophila eye, clones of cells that are homozygous for partial loss of function alleles of Uba1 show defects in apoptosis. Moreover, clones homozygous for stronger or complete loss of function alleles of Uba1, that are predicted to have a global defect on ubiquitination, survive poorly but are able to stimulate the overgrowth of adjacent wild-type tissue. Experiments with mammalian cells show that reducing the level of RNA of the mammalian Uba1 ortholog, UBE1, also results in increased expression of specific growth factor genes. Our studies show that a reduction in E1 activity can promote tissue growth in a multicellular organism and raise the possibility that changes in E1 activity may occur during normal development or in cancer.
Insights
Reduced activity of the E1 enzyme (Uba1) in Drosophila causes cell defects and promotes adjacent tissue growth. This suggests E1 enzyme activity changes may influence development and cancer.
Area of Science:
- Cell Biology
- Developmental Biology
- Biochemistry
Background:
- Protein ubiquitination regulates critical cellular processes like apoptosis and cell cycle.
- Regulation primarily occurs at E2 or E3 enzyme levels, with E1 enzymes initiating the ubiquitination cascade.
- Previous studies linked E1 enzyme disruption to cell-cycle arrest in yeast and mammalian cells.
Purpose of the Study:
- Investigate the role of the E1 enzyme (Uba1) in Drosophila development, specifically focusing on tissue overgrowth.
- Determine the effects of altered Uba1 activity on apoptosis and cell survival in developing tissues.
- Explore the potential link between reduced E1 activity and growth factor gene expression in mammalian cells.
Main Methods:
- Conducted a genetic screen in Drosophila to identify mutations affecting tissue growth.
- Utilized Drosophila Uba1 loss-of-function alleles to study effects on apoptosis and tissue overgrowth in the developing eye.
- Performed experiments on mammalian cells to assess the impact of UBE1 (Uba1 ortholog) RNA reduction on growth factor gene expression.
Main Results:
- Mutations in Drosophila Uba1 gene were identified in a screen for tissue overgrowth.
- Partial Uba1 loss-of-function clones in Drosophila eyes exhibited apoptosis defects.
- Stronger Uba1 loss-of-function clones survived poorly but stimulated overgrowth in adjacent wild-type tissue.
- Reduced UBE1 RNA levels in mammalian cells led to increased expression of specific growth factor genes.
Conclusions:
- Reduced E1 enzyme activity can promote tissue growth in a multicellular organism.
- Altered E1 activity may play a role in normal development and cancer progression.
- The findings highlight a potential link between E1 enzyme function and uncontrolled cell proliferation.
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