Persistent replicative stress alters polycomb phenotypes and tissue homeostasis in Drosophila melanogaster

Cell Rep. 2014 May 8;7(3):859-70. doi: 10.1016/j.celrep.2014.03.042. Epub 2014 Apr 18.


Polycomb group (PcG) proteins establish and maintain genetic programs that regulate cell-fate decisions. Drosophila multi sex combs (mxc) was categorized as a PcG gene based on a classical Polycomb phenotype and genetic interactions; however, a mechanistic connection between Polycomb and Mxc has not been elucidated. Hypomorphic alleles of mxc are characterized by male and female sterility and ectopic sex combs. Mxc is an important regulator of histone synthesis, and we find that increased levels of the core histone H3 in mxc mutants result in replicative stress and a persistent DNA damage response (DDR). Germline loss, ectopic sex combs and the DDR are suppressed by reducing H3 in mxc mutants. Conversely, mxc phenotypes are enhanced when the DDR is abrogated. Importantly, replicative stress induced by hydroxyurea treatment recapitulated mxc germline phenotypes. These data reveal how persistent replicative stress affects gene expression, tissue homeostasis, and maintenance of cellular identity in vivo.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Cell Lineage
  • DNA Repair
  • DNA Replication / drug effects
  • Drosophila Proteins / antagonists & inhibitors
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / metabolism*
  • Female
  • Germ Cells / cytology
  • Germ Cells / metabolism
  • Histones / genetics
  • Histones / metabolism
  • Hydroxyurea / pharmacology
  • Male
  • Phenotype
  • Phosphorylation
  • Polycomb-Group Proteins / antagonists & inhibitors
  • Polycomb-Group Proteins / genetics
  • Polycomb-Group Proteins / metabolism*
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Testis / cytology
  • Tumor Suppressor Proteins / antagonists & inhibitors
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*


  • Drosophila Proteins
  • Histones
  • Mxc protein, Drosophila
  • Polycomb-Group Proteins
  • RNA, Small Interfering
  • Tumor Suppressor Proteins
  • Hydroxyurea