Low CDK Activity and Enhanced Degradation by APC/C
Fanghua Li1,2, Emil Mladenov1,3, Yanjie Sun1,2
1Institute of Medical Radiation Biology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany.
Cells
|June 10, 2023
Summary
Alternative-end joining (alt-EJ) DNA repair is regulated by CtIP levels, which are low in G1 and undetectable in G0 cells due to degradation. Suppressing CtIP degradation restores alt-EJ in G0 cells, maintaining genomic stability.
Area of Science:
- DNA repair mechanisms
- Genomic stability
- Cell cycle regulation
Background:
- Alternative-end joining (alt-EJ) is an error-prone DNA double-strand break (DSB) repair pathway active when canonical pathways (c-NHEJ, HR) fail.
- Alt-EJ efficiency is cell cycle-dependent, peaking in G2, reduced in G1, and minimal in quiescent G0 cells.
- The precise regulation of alt-EJ across cell cycle phases, particularly in G0, remains unclear.
Purpose of the Study:
- To investigate the mechanism regulating alt-EJ in G1- and G0-phase cells.
- To identify the key factors controlling alt-EJ during DNA double-strand break repair in quiescent cells.
- To understand how genomic stability is maintained in non-cycling cells.
Main Methods:
- Comparison of alt-EJ activity in G1 and G0 cells following ionizing radiation (IR) exposure.
- Assessment of CtIP (C-terminal-binding protein-interacting protein) levels and its role in DNA end resection.
- Pharmacological inhibition of CtIP degradation (bortezomib) and genetic depletion of CDH1 to rescue CtIP expression in G0 cells.
- Analysis of CDK (cyclin-dependent kinase) phosphorylation of CtIP in G0 cells.
Main Results:
- CtIP-dependent DNA end resection is identified as the critical regulator of alt-EJ in G1 and G0 cells.
- Low CtIP levels in G1 cells permit limited resection and alt-EJ compared to G2 cells.
- CtIP is undetectable in G0 cells due to APC/C-mediated degradation, significantly suppressing alt-EJ.
- Inhibition of CtIP degradation or CDH1 depletion restores CtIP and alt-EJ activity in G0 cells.
- CtIP activation in G0 requires CDK-dependent phosphorylation, primarily by CDK4/6.
Conclusions:
- Suppression of mutagenic alt-EJ in G0-phase cells is achieved through the regulated degradation of CtIP.
- This mechanism is crucial for maintaining genomic stability in the large population of non-cycling cells in higher eukaryotes.
- CtIP levels and activity are tightly controlled throughout the cell cycle to balance DNA repair fidelity and genomic integrity.
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