Genome-wide functional analysis of human cell-cycle regulators

Proc Natl Acad Sci U S A. 2006 Oct 3;103(40):14819-24. doi: 10.1073/pnas.0604320103. Epub 2006 Sep 25.


Human cells have evolved complex signaling networks to coordinate the cell cycle. A detailed understanding of the global regulation of this fundamental process requires comprehensive identification of the genes and pathways involved in the various stages of cell-cycle progression. To this end, we report a genome-wide analysis of the human cell cycle, cell size, and proliferation by targeting >95% of the protein-coding genes in the human genome using small interfering RNAs (siRNAs). Analysis of >2 million images, acquired by quantitative fluorescence microscopy, showed that depletion of 1,152 genes strongly affected cell-cycle progression. These genes clustered into eight distinct phenotypic categories based on phase of arrest, nuclear area, and nuclear morphology. Phase-specific networks were built by interrogating knowledge-based and physical interaction databases with identified genes. Genome-wide analysis of cell-cycle regulators revealed a number of kinase, phosphatase, and proteolytic proteins and also suggests that processes thought to regulate G(1)-S phase progression like receptor-mediated signaling, nutrient status, and translation also play important roles in the regulation of G(2)/M phase transition. Moreover, 15 genes that are integral to TNF/NF-kappaB signaling were found to regulate G(2)/M, a previously unanticipated role for this pathway. These analyses provide systems-level insight into both known and novel genes as well as pathways that regulate cell-cycle progression, a number of which may provide new therapeutic approaches for the treatment of cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / metabolism*
  • Cluster Analysis
  • Cytokinesis / genetics
  • Gene Expression
  • Genes, cdc
  • Genome, Human / genetics*
  • Genomic Library
  • Humans
  • Mitosis / genetics
  • Neoplasms / genetics
  • Phenotype
  • Protein Interaction Mapping
  • RNA Interference
  • RNA, Small Interfering / metabolism


  • Cell Cycle Proteins
  • RNA, Small Interfering