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PP2A licenses the FANCD2/FANCI complex for chromosome loading.

Di Yang1, Fengxiang Bai1, David Lopez Martinez1

  • 1Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK.

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|November 13, 2024
PubMed
Summary

A protein phosphatase 2A (PP2A) complex activates the Fanconi anemia (FA) pathway by dephosphorylating FANCD2, enabling its loading onto chromosomes to repair DNA damage.

Keywords:
CP: Molecular biologyDNA interstrand crosslink repairFANCD2FANCD2/FANCI complexFanconi anemiaICL repairPP2Adephosphorylationgenome stabilityphosphorylation

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Area of Science:

  • Molecular Biology
  • DNA Repair Mechanisms
  • Cellular Signaling

Background:

  • The Fanconi anemia (FA) pathway is crucial for repairing DNA interstrand crosslinks (ICLs).
  • The FANCD2/FANCI complex is central to the FA pathway and requires chromosomal loading for activation.
  • Regulation of FANCD2/FANCI loading is essential for DNA damage response.

Purpose of the Study:

  • To identify the phosphatase responsible for dephosphorylating FANCD2.
  • To elucidate the mechanism by which FANCD2 is licensed for chromosomal loading.
  • To understand the role of PP2A in activating the Fanconi anemia pathway.

Main Methods:

  • Identification and purification of a PP2A phosphatase complex.
  • In vitro reconstitution of a coupled dephosphorylation-ubiquitination reaction.
  • Super-resolution live-cell single-molecule tracking of PP2A activity.

Main Results:

  • A PP2A phosphatase complex specifically dephosphorylates an inhibitory cluster in FANCD2.
  • PP2A is required for FANCD2/FANCI monoubiquitination and chromosomal loading.
  • PP2A activation of the FA pathway is essential for cellular resistance to ICL-forming drugs.

Conclusions:

  • PP2A directly licenses FANCD2/FANCI complex loading onto chromosomes in response to DNA damage.
  • PP2A acts as a critical switch to activate the Fanconi anemia pathway.
  • This study uncovers a novel regulatory mechanism for DNA repair pathway activation.