Small molecules that delay S phase suppress a zebrafish bmyb mutant

Nat Chem Biol. 2005 Dec;1(7):366-70. doi: 10.1038/nchembio749.


Bmyb is a ubiquitously expressed transcription factor involved in cellular proliferation and cancer. Loss of bmyb function in the zebrafish mutant crash&burn (crb) results in decreased cyclin B1 expression, mitotic arrest and genome instability. These phenotypic observations in crb mutants could be attributed to the decreased expression of cyclin B1, a cell-cycle regulatory protein that is responsible for driving cell progression from G2 through mitosis. To identify small molecules that interact with the bmyb pathway, we developed an embryo-based suppressor screening strategy. In 16 weeks we screened a diverse approximately 16,000 compound library, and discovered one previously unknown compound, persynthamide (psy, 1), that suppressed bmyb-dependent mitotic defects. Psy-treated embryos showed an S-phase delay, and knockdown of the cell-cycle checkpoint regulator ataxia telangiectasia--and Rad-related kinase (ATR) abrogated the suppression of crb. The DNA synthesis inhibitors aphidicolin (2) and hydroxyurea (3) also suppressed crb. S-phase inhibition upregulated cyclin B1 mRNA, promoting the progression of cells through mitosis. Our study demonstrates that chemical suppressor screening in zebrafish can identify compounds with cell-cycle activity and can be used to identify pathways that interact with specific cell-cycle phenotypes.

Publication types

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

MeSH terms

  • Adamantane / analogs & derivatives*
  • Adamantane / chemistry
  • Adamantane / pharmacology
  • Animals
  • Cell Cycle / drug effects
  • Cell Cycle / physiology
  • Cyclin B / drug effects
  • Cyclin B / genetics
  • Cyclin B1
  • Gene Expression Regulation, Developmental / drug effects
  • Mitosis / drug effects
  • Mutation*
  • Phenotype
  • Proto-Oncogene Proteins c-myb / genetics*
  • Proto-Oncogene Proteins c-myb / metabolism
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • RNA, Messenger / drug effects
  • RNA, Messenger / genetics
  • S Phase / drug effects
  • S Phase / genetics*
  • Zebrafish / embryology
  • Zebrafish / genetics*
  • Zebrafish / growth & development


  • Cyclin B
  • Cyclin B1
  • Proto-Oncogene Proteins c-myb
  • Pyridines
  • RNA, Messenger
  • persynthamide
  • Adamantane