%0 Journal Article
%A Li, Fanghua
%A Mladenov, Emil
%A Sun, Yanjie
%A Soni, Aashish
%A Stuschke, Martin
%A Timmermann, Beate
%A Iliakis, George
%T Low CDK Activity and Enhanced Degradation by APC/CCDH1 Abolishes CtIP Activity and Alt-EJ in Quiescent Cells.
%J Cells
%V 12
%N 11
%@ 2073-4409
%C Basel
%I MDPI
%M DKFZ-2023-01156
%P 1530
%D 2023
%X 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.
%K Phosphorylation
%K Nuclear Proteins: metabolism
%K DNA Repair
%K DNA Breaks, Double-Stranded
%K Cell Cycle Checkpoints
%K APC/C (Other)
%K CDKs (Other)
%K CtIP (Other)
%K DNA end-resection (Other)
%K DNA repair (Other)
%K RPA (Other)
%K alt-EJ (Other)
%K ionizing radiation (Other)
%K pulsed-field gel electrophoresis (Other)
%K repair of DNA double-strand breaks (Other)
%K Nuclear Proteins (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:37296650
%2 pmc:PMC10252496
%R 10.3390/cells12111530
%U https://inrepo02.dkfz.de/record/276775