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FANCD2 is a target for caspase 3 during DNA damage-induced apoptosis

Wataru Sakai1, Kaoru Sugasawa1

  • 1Biosignal Research Center, Organization of Advanced Science and Technology, Kobe University, 1-1 Rokkodai-cho, Nada, Kobe, Hyogo 657-8501, Japan; Department of Biology, Graduate School of Science, Kobe University, 1-1 Rokkodai-cho, Nada, Kobe, Hyogo 657-8501, Japan.

FEBS Letters
|September 2, 2014
PubMed

Insights

Fanconi anemia (FA) pathway protein FANCD2 is degraded by caspase 3 during DNA damage-induced apoptosis. This novel FANCD2 regulation by caspase 3 occurs independently of the FA core complex and FANCD2 ubiquitylation, and is stimulated by p53.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Cancer Research

Background:

  • The Fanconi anemia (FA) pathway is critical for maintaining hematopoietic stem cells and preventing cancer.
  • FANCD2 is a key protein within the FA pathway, but its precise function remains incompletely understood.

Purpose of the Study:

  • To elucidate the function of FANCD2, particularly its regulation during cellular stress.
  • To investigate the interaction between FANCD2 and apoptotic pathways.

Main Methods:

  • Identification of FANCD2 as a substrate for caspase 3.
  • Characterization of FANCD2 cleavage by caspase 3, including the role of the FA core complex, FANCD2 mono-ubiquitylation, and p53.
  • Site-directed mutagenesis to create a caspase-resistant FANCD2 mutant.
  • Generation of stable cell lines expressing the mutant FANCD2.

Main Results:

  • FANCD2 is a novel and specific substrate of caspase 3.
  • Caspase 3-mediated cleavage of FANCD2 occurs independently of the FA core complex and FANCD2 mono-ubiquitylation.
  • p53 stimulates the cleavage of FANCD2 by caspase 3.
  • Specific cleavage sites within FANCD2 were identified.
  • Expression of a caspase-resistant FANCD2 mutant was successfully established.

Conclusions:

  • FANCD2 undergoes caspase-mediated degradation as a regulatory mechanism during apoptosis induced by DNA damage.
  • This finding reveals a new layer of control over FANCD2 function in response to cellular stress.
  • The regulation of FANCD2 by caspase 3, independent of canonical FA pathway activation, suggests diverse roles in cell fate determination.
Keywords:
ApoptosisCaspaseDNA repairFANCD2Fanconi anemia

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