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Genome-wide Protein-protein Interaction Screening by Protein-fragment Complementation Assay PCA in Living Cells
Published on: March 3, 2015
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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.
Cell Reports
|November 13, 2024
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.
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.
Keywords:
CP: Molecular biologyDNA interstrand crosslink repairFANCD2FANCD2/FANCI complexFanconi anemiaICL repairPP2Adephosphorylationgenome stabilityphosphorylationMore Related Videos
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