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Differential functions of FANCI and FANCD2 ubiquitination stabilize ID2 complex on DNA

Martin L Rennie1, Kimon Lemonidis1, Connor Arkinson1

  • 1Institute of Molecular Cell and Systems Biology, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.

EMBO Reports
|June 9, 2020
PubMed

Insights

Ubiquitination of FANCD2 and FANCI in the Fanconi anaemia pathway stabilizes the ID2 complex to encircle DNA. This crucial step enhances DNA repair and replication stress response mechanisms.

Area of Science:

  • Molecular Biology
  • Genetics
  • Biochemistry

Background:

  • The Fanconi anaemia (FA) pathway is essential for repairing DNA interstrand crosslinks.
  • This pathway also responds to other replication stress signals.
  • Monoubiquitination of the ID2 complex (FANCI-FANCD2) is a key FA pathway step with unknown function.

Purpose of the Study:

  • To elucidate the molecular function of FANCI and FANCD2 monoubiquitination.
  • To understand how these modifications impact the ID2 complex's role in DNA repair.

Main Methods:

  • Biochemical assays to study protein interactions and DNA binding.
  • Structural analysis to observe conformational changes in the ID2 complex.
  • Site-directed mutagenesis to investigate the role of specific residues.

Main Results:

  • FANCD2 ubiquitination increases the ID2 complex's affinity for double-stranded DNA.
  • This modification induces a large conformational change, enabling the complex to encircle DNA via a new interface.
  • FANCI ubiquitination protects FANCD2-ubiquitin from deubiquitination by USP1-UAF1.

Conclusions:

  • Both FANCI and FANCD2 ubiquitination stabilize a DNA-encircling conformation of the ID2 complex.
  • These post-translational modifications are critical for the FA pathway's function in DNA repair and replication stress response.
Keywords:
DNA repairFanconi anaemiadeubiquitinationprotein-DNA interactionsubiquitin

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