Home > Publications database > Low CDK Activity and Enhanced Degradation by APC/CCDH1 Abolishes CtIP Activity and Alt-EJ in Quiescent Cells. > print

001     276775
005     20240229162340.0
024 7 _ |a 10.3390/cells12111530
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037 _ _ |a DKFZ-2023-01156
041 _ _ |a English
082 _ _ |a 570
100 1 _ |a Li, Fanghua
|0 0000-0001-7610-8489
|b 0
245 _ _ |a Low CDK Activity and Enhanced Degradation by APC/CCDH1 Abolishes CtIP Activity and Alt-EJ in Quiescent Cells.
260 _ _ |a Basel
|c 2023
|b MDPI
336 7 _ |a article
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336 7 _ |a ARTICLE
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336 7 _ |a Journal Article
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520 _ _ |a 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.
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588 _ _ |a Dataset connected to CrossRef, PubMed, , Journals: inrepo02.dkfz.de
650 _ 7 |a APC/C
|2 Other
650 _ 7 |a CDKs
|2 Other
650 _ 7 |a CtIP
|2 Other
650 _ 7 |a DNA end-resection
|2 Other
650 _ 7 |a DNA repair
|2 Other
650 _ 7 |a RPA
|2 Other
650 _ 7 |a alt-EJ
|2 Other
650 _ 7 |a ionizing radiation
|2 Other
650 _ 7 |a pulsed-field gel electrophoresis
|2 Other
650 _ 7 |a repair of DNA double-strand breaks
|2 Other
650 _ 7 |a Nuclear Proteins
|2 NLM Chemicals
650 _ 2 |a Phosphorylation
|2 MeSH
650 _ 2 |a Nuclear Proteins: metabolism
|2 MeSH
650 _ 2 |a DNA Repair
|2 MeSH
650 _ 2 |a DNA Breaks, Double-Stranded
|2 MeSH
650 _ 2 |a Cell Cycle Checkpoints
|2 MeSH
700 1 _ |a Mladenov, Emil
|b 1
700 1 _ |a Sun, Yanjie
|b 2
700 1 _ |a Soni, Aashish
|0 0000-0001-9696-1006
|b 3
700 1 _ |a Stuschke, Martin
|0 P:(DE-HGF)0
|b 4
700 1 _ |a Timmermann, Beate
|0 P:(DE-HGF)0
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700 1 _ |a Iliakis, George
|0 0000-0002-1152-5342
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773 _ _ |a 10.3390/cells12111530
|g Vol. 12, no. 11, p. 1530 -
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