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Updated: Mar 19, 2026
A Drosophila Model to Study Wound-induced Polyploidization
Published on: June 9, 2020
Proliferation of Double-Strand Break-Resistant Polyploid Cells Requires Drosophila FANCD2
Heidi S Bretscher1, Donald T Fox1
1Department of Pharmacology & Cancer Biology, Duke University School of Medicine, DUMC Box 3813, Durham, NC 27710, USA.
Abstract:
Conserved DNA-damage responses (DDRs) sense genome damage and prevent mitosis of broken chromosomes. How cells lacking DDRs cope with broken chromosomes during mitosis is poorly understood. DDRs are frequently inactivated in cells with extra genomes (polyploidy), suggesting that study of polyploidy can reveal how cells with impaired DDRs/genome damage continue dividing. Here, we show that continued division and normal organ development occurs in polyploid, DDR-impaired Drosophila papillar cells. As papillar cells become polyploid, they naturally accumulate broken acentric chromosomes but do not apoptose/arrest the cell cycle. To survive mitosis with acentric chromosomes, papillar cells require Fanconi anemia proteins FANCD2 and FANCI, as well as Blm helicase, but not canonical DDR signaling. FANCD2 acts independently of previous S phases to promote alignment and segregation of acentric DNA produced by double-strand breaks, thus avoiding micronuclei and organ malformation. Because polyploidy and impaired DDRs can promote cancer, our findings provide insight into disease-relevant DNA-damage tolerance mechanisms.
Insights
Cells with impaired DNA-damage responses (DDRs) can divide with broken chromosomes during polyploidy. Fanconi anemia proteins FANCD2/FANCI and Blm helicase enable survival, offering insights into cancer-related DNA damage tolerance.
Area of Science:
- Cell Biology
- Genetics
- Developmental Biology
Background:
- DNA-damage responses (DDRs) are crucial for preventing mitosis with damaged chromosomes.
- Polyploidy, often associated with cancer, frequently involves inactivated DDRs, yet how these cells divide remains unclear.
Purpose of the Study:
- To investigate how cells lacking functional DDRs cope with broken chromosomes during mitosis in polyploid cells.
- To identify the molecular mechanisms enabling cell division and normal organ development in polyploid, DDR-impaired cells.
Main Methods:
- Utilized Drosophila melanogaster as a model organism.
- Examined polyploid papillar cells accumulating broken acentric chromosomes.
- Assessed the requirement for Fanconi anemia proteins (FANCD2, FANCI) and Blm helicase in DDR-impaired cells.
Main Results:
- Polyploid Drosophila papillar cells with impaired DDRs survive mitosis despite accumulating broken acentric chromosomes.
- Fanconi anemia proteins FANCD2 and FANCI, along with Blm helicase, are essential for this survival.
- FANCD2 facilitates the alignment and segregation of acentric DNA, preventing micronuclei formation and organ malformation, independent of prior S-phase activity.
Conclusions:
- Cells can divide and develop normally with broken chromosomes if DDRs are impaired, provided specific DNA-damage tolerance pathways are active.
- Findings illuminate disease-relevant DNA-damage tolerance mechanisms in polyploid cells, with implications for cancer biology.
