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@ARTICLE{Li:276775,
author = {F. Li and E. Mladenov and Y. Sun and A. Soni and M.
Stuschke$^*$ and B. Timmermann$^*$ and G. Iliakis},
title = {{L}ow {CDK} {A}ctivity and {E}nhanced {D}egradation by
{APC}/{CCDH}1 {A}bolishes {C}t{IP} {A}ctivity and {A}lt-{EJ}
in {Q}uiescent {C}ells.},
journal = {Cells},
volume = {12},
number = {11},
issn = {2073-4409},
address = {Basel},
publisher = {MDPI},
reportid = {DKFZ-2023-01156},
pages = {1530},
year = {2023},
abstract = {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.},
keywords = {Phosphorylation / Nuclear Proteins: metabolism / DNA Repair
/ DNA Breaks, Double-Stranded / Cell Cycle Checkpoints /
APC/C (Other) / CDKs (Other) / CtIP (Other) / DNA
end-resection (Other) / DNA repair (Other) / RPA (Other) /
alt-EJ (Other) / ionizing radiation (Other) / pulsed-field
gel electrophoresis (Other) / repair of DNA double-strand
breaks (Other) / Nuclear Proteins (NLM Chemicals)},
cin = {ED01},
ddc = {570},
cid = {I:(DE-He78)ED01-20160331},
pnm = {899 - ohne Topic (POF4-899)},
pid = {G:(DE-HGF)POF4-899},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:37296650},
pmc = {pmc:PMC10252496},
doi = {10.3390/cells12111530},
url = {https://inrepo02.dkfz.de/record/276775},
}