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A FANCD2 domain activates Tip60-dependent apoptosis

James Hejna1, Donald Bruun, Daniel Pauw

  • 1Department of Molecular and Medical Genetics, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239-3098, USA.

Cell Biology International
|May 29, 2010
PubMed

Insights

Exogenously expressed Fanconi anemia (FA) FANCD2 protein triggers apoptosis via interaction with Tip60, specifically involving exons 10-13. Depleting Tip60 allows stable, high-level FANCD2 expression, revealing Tip60

Area of Science:

  • Molecular Biology
  • DNA Repair Mechanisms
  • Cellular Apoptosis

Background:

  • Fanconi anemia (FA) protein FANCD2 is crucial for DNA interstrand cross-link repair.
  • Establishing cell lines with exogenous FANCD2 expression is challenging compared to other DNA repair genes.

Purpose of the Study:

  • To investigate the mechanism by which exogenous nuclear FANCD2 expression impacts cellular viability.
  • To identify the specific regions and interactions of FANCD2 responsible for cellular responses.

Main Methods:

  • Transformed normal human fibroblasts were used to express exogenous FANCD2.
  • FANCD2 constructs with deletions in exons 10-13 were generated.
  • Interaction between FANCD2 and Tip60 was assessed.
  • Tip60 depletion was performed to evaluate its effect on FANCD2 expression and apoptosis.

Main Results:

  • Exogenous nuclear FANCD2 expression induced apoptosis in human fibroblasts.
  • Apoptosis was specifically dependent on exons 10-13 of FANCD2, a region critical for Tip60 interaction.
  • Deletion of exons 10-13 abolished both Tip60 interaction and the apoptotic response.
  • Stable, high-level FANCD2 expression was achieved upon Tip60 depletion.

Conclusions:

  • FANCD2-induced apoptosis requires a specific interaction with the histone acetyltransferase Tip60.
  • The interaction between FANCD2 (exons 10-13) and Tip60 is essential for triggering apoptosis.
  • Tip60 plays a critical role in mediating the cellular response to exogenous FANCD2 expression.

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