Proliferation of Double-Strand Break-Resistant Polyploid Cells Requires Drosophila FANCD2.
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.
Department of Pharmacology & Cancer Biology, Duke University School of Medicine, DUMC Box 3813, Durham, NC 27710, USA.
Heidi S
HS
Bretscher
Department of Pharmacology & Cancer Biology, Duke University School of Medicine, DUMC Box 3813, Durham, NC 27710, USA. Electronic address: don.fox@duke.edu.
Donald T
DT
Fox
D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D049109:Cell Proliferation / Q000528:radiation effects; D002470:Cell Survival / Q000528:radiation effects; D020090:Chromosome Segregation / Q000528:radiation effects; D059006:Chromosomes, Insect / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D004265:DNA Helicases / Q000378:metabolism; D004260:DNA Repair / Q000528:radiation effects; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology* / Q000378:metabolism* / Q000528:radiation effects; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000378:metabolism*; D048629:Micronuclei, Chromosome-Defective / Q000528:radiation effects; D010641:Phenotype; D011123:Polyploidy; D011839:Radiation, Ionizing; D016196:S Phase / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D029721:Drosophila Proteins; C499906:Fancd2 protein, Drosophila; D052236:Fanconi Anemia Complementation Group D2 Protein; D016159:Tumor Suppressor Protein p53; D004247:DNA; D004265:DNA Helicases; C470639:blm protein, Drosophila
FANCD2; endocycle; polyploidy