A novel transcriptional cascade is involved in Fzr-mediated endoreplication

Nucleic Acids Res. 2020 May 7;48(8):4214-4229. doi: 10.1093/nar/gkaa158.


Endoreplication, known as endocycle, is a variant of the cell cycle that differs from mitosis and occurs in specific tissues of different organisms. Endoreplicating cells generally undergo multiple rounds of genome replication without chromosome segregation. Previous studies demonstrated that Drosophila fizzy-related protein (Fzr) and its mammalian homolog Cdh1 function as key regulators of endoreplication entrance by activating the anaphase-promoting complex/cyclosome to initiate the ubiquitination and subsequent degradation of cell cycle factors such as Cyclin B (CycB). However, the molecular mechanism underlying Fzr-mediated endoreplication is not completely understood. In this study, we demonstrated that the transcription factor Myc acts downstream of Fzr during endoreplication in Drosophila salivary gland. Mechanistically, Fzr interacts with chromatin-associated histone H2B to enhance H2B ubiquitination in the Myc promoter and promotes Myc transcription. In addition to negatively regulating CycB transcription, the Fzr-ubiquitinated H2B (H2Bub)-Myc signaling cascade also positively regulates the transcription of the MCM6 gene that is involved in DNA replication by directly binding to specific motifs within their promoters. We further found that the Fzr-H2Bub-Myc signaling cascade regulating endoreplication progression is conserved between insects and mammalian cells. Altogether, our work uncovers a novel transcriptional cascade that is involved in Fzr-mediated endoreplication.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cdh1 Proteins / metabolism*
  • Cell Line
  • Cyclin B / genetics
  • DNA Replication
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Drosophila / genetics
  • Drosophila / metabolism
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Endoreduplication*
  • Gene Expression Regulation*
  • HEK293 Cells
  • Histones / metabolism
  • Humans
  • Minichromosome Maintenance Complex Component 6 / genetics
  • Promoter Regions, Genetic
  • Salivary Glands / metabolism
  • Signal Transduction
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Ubiquitination


  • Cdh1 Proteins
  • CycB protein, Drosophila
  • Cyclin B
  • DNA-Binding Proteins
  • Drosophila Proteins
  • Histones
  • Myc protein, Drosophila
  • Transcription Factors
  • fzr protein, Drosophila
  • Mcm6 protein, Drosophila
  • Minichromosome Maintenance Complex Component 6