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Structural insights into the DNA-binding specificity of E2F family transcription factors

Ekaterina Morgunova1, Yimeng Yin1, Arttu Jolma1

  • 1Department of Biosciences and Nutrition, Karolinska Institutet, SE 141 83 Stockholm, Sweden.

Nature Communications
|December 4, 2015
PubMed

Insights

Atypical E2F proteins, like E2F8, have two DNA-binding domains and repress cell cycle genes. This study reveals the atomic structure of E2F8 bound to DNA, explaining its repressive mechanism.

Area of Science:

  • Molecular Biology
  • Genetics
  • Structural Biology

Background:

  • The cell cycle in mammals is regulated by E2F transcription factors.
  • Typical E2Fs form heterodimers with DP proteins.
  • Atypical E2Fs (E2F7, E2F8) possess two DNA-binding domains and function as repressors.

Purpose of the Study:

  • To elucidate the repression mechanism of atypical E2Fs.
  • To determine the atomic structure of E2F8 in complex with DNA.

Main Methods:

  • X-ray crystallography to resolve E2F8-DNA structure.
  • Molecular dynamics simulations.
  • Biochemical affinity measurements.
  • Chromatin immunoprecipitation (ChIP).

Main Results:

  • The first crystal structure of a two-DNA-binding domain E2F protein (E2F8) bound to DNA was determined.
  • E2F8's DNA-binding domains structurally resemble those of typical E2F and DP proteins.
  • Both atypical and typical E2Fs bind to similar DNA sequences in vitro and in vivo.

Conclusions:

  • Atypical E2Fs bind DNA via two distinct domains.
  • This binding mechanism explains how E2F7 and E2F8 repress canonical E2F target genes.
  • Atypical E2Fs negatively regulate cell cycle progression.

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