TY  - JOUR
AU  - Li, Fanghua
AU  - Mladenov, Emil
AU  - Sun, Yanjie
AU  - Soni, Aashish
AU  - Stuschke, Martin
AU  - Timmermann, Beate
AU  - Iliakis, George
TI  - Low CDK Activity and Enhanced Degradation by APC/CCDH1 Abolishes CtIP Activity and Alt-EJ in Quiescent Cells.
JO  - Cells
VL  - 12
IS  - 11
SN  - 2073-4409
CY  - Basel
PB  - MDPI
M1  - DKFZ-2023-01156
SP  - 1530
PY  - 2023
AB  - Alt-EJ is an error-prone DNA double-strand break (DSBs) repair pathway coming to the fore when first-line repair pathways, c-NHEJ and HR, are defective or fail. It is thought to benefit from DNA end-resection-a process whereby 3' single-stranded DNA-tails are generated-initiated by the CtIP/MRE11-RAD50-NBS1 (MRN) complex and extended by EXO1 or the BLM/DNA2 complex. The connection between alt-EJ and resection remains incompletely characterized. Alt-EJ depends on the cell cycle phase, is at maximum in G2-phase, substantially reduced in G1-phase and almost undetectable in quiescent, G0-phase cells. The mechanism underpinning this regulation remains uncharacterized. Here, we compare alt-EJ in G1- and G0-phase cells exposed to ionizing radiation (IR) and identify CtIP-dependent resection as the key regulator. Low levels of CtIP in G1-phase cells allow modest resection and alt-EJ, as compared to G2-phase cells. Strikingly, CtIP is undetectable in G0-phase cells owing to APC/C-mediated degradation. The suppression of CtIP degradation with bortezomib or CDH1-depletion rescues CtIP and alt-EJ in G0-phase cells. CtIP activation in G0-phase cells also requires CDK-dependent phosphorylation by any available CDK but is restricted to CDK4/6 at the early stages of the normal cell cycle. We suggest that suppression of mutagenic alt-EJ in G0-phase is a mechanism by which cells of higher eukaryotes maintain genomic stability in a large fraction of non-cycling cells in their organisms.
KW  - Phosphorylation
KW  - Nuclear Proteins: metabolism
KW  - DNA Repair
KW  - DNA Breaks, Double-Stranded
KW  - Cell Cycle Checkpoints
KW  - APC/C (Other)
KW  - CDKs (Other)
KW  - CtIP (Other)
KW  - DNA end-resection (Other)
KW  - DNA repair (Other)
KW  - RPA (Other)
KW  - alt-EJ (Other)
KW  - ionizing radiation (Other)
KW  - pulsed-field gel electrophoresis (Other)
KW  - repair of DNA double-strand breaks (Other)
KW  - Nuclear Proteins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:37296650
C2  - pmc:PMC10252496
DO  - DOI:10.3390/cells12111530
UR  - https://inrepo02.dkfz.de/record/276775
ER  -