Proliferation of Double-Strand Break-Resistant Polyploid Cells Requires Drosophila FANCD2

Heidi S. Bretscher, Donald T. Fox

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)444-457
Number of pages14
JournalDevelopmental Cell
Volume37
Issue number5
DOIs
StatePublished - 2016

Bibliographical note

Funding Information:
Reagents were kindly provided by Bloomington and Vienna Stock Centers, Allen Bale, Roger Karess, Dan Kiehart, Christian Lehner, Jeff Sekelsky (who provided the fancm deletion stock before publication), Tin-Tin Su (who also provided technical advice on IR), William Sullivan (who also provided technical advice on imaging tethers), and Will Wood. We thank David Kirsch, Daniel Lew, and members of the Fox and MacAlpine laboratories for valuable comments on the manuscript. D.F. is supported by a Pew Scholar Award and NIH grant GM118447 . H.B. is supported by NIH grant CA186545 .

Publisher Copyright:
© 2016 Elsevier Inc.

Keywords

  • FANCD2
  • endocycle
  • polyploidy

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