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PPM1D activity promotes the replication stress caused by cyclin E1 overexpression
AS. Martinikova, M. Stoyanov, A. Oravetzova, YP. Kok, S. Yu, J. Dobrovolna, P. Janscak, M. van Vugt, L. Macurek
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články
Grantová podpora
20-11931S
Grantová Agentura České Republiky
LM2018129
Ministerstvo Školství, Mládeže a Tělovýchovy
LTAUSA19096
Ministerstvo Školství, Mládeže a Tělovýchovy
LX22NPO5102
Ministerstvo Školství, Mládeže a Tělovýchovy
CZ.02.1.01/0.0/0.0/18_046/0016045
Ministerstvo Školství, Mládeže a Tělovýchovy
KFS-5484-02-2022
Swiss Cancer League
21-22593X
Czech Science Foundation
68378050-KAV-NPUI
RVO
CEP - Centrální evidence projektů
PubMed Central od 2007
Europe PubMed Central od 2007
ProQuest Central od 2007-06-01
Wiley-Blackwell Open Access Titles od 2007
ROAD: Directory of Open Access Scholarly Resources od 2007
Odkazy
PubMed
37067201
DOI
10.1002/1878-0261.13433
Knihovny.cz E-zdroje
- MeSH
- cyklin E genetika metabolismus MeSH
- lidé MeSH
- nádorový supresorový protein p53 * genetika metabolismus MeSH
- nádory * MeSH
- nestabilita genomu MeSH
- proteinfosfatasa 2C genetika metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Oncogene-induced replication stress has been recognized as a major cause of genome instability in cancer cells. Increased expression of cyclin E1 caused by amplification of the CCNE1 gene is a common cause of replication stress in various cancers. Protein phosphatase magnesium-dependent 1 delta (PPM1D) is a negative regulator of p53 and has been implicated in termination of the cell cycle checkpoint. Amplification of the PPM1D gene or frameshift mutations in its final exon promote tumorigenesis. Here, we show that PPM1D activity further increases the replication stress caused by overexpression of cyclin E1. In particular, we demonstrate that cells expressing a truncated mutant of PPM1D progress faster from G1 to S phase and fail to complete licensing of the replication origins. In addition, we show that transcription-replication collisions and replication fork slowing caused by CCNE1 overexpression are exaggerated in cells expressing the truncated PPM1D. Finally, replication speed and accumulation of focal DNA copy number alterations caused by induction of CCNE1 expression was rescued by pharmacological inhibition of PPM1D. We propose that increased activity of PPM1D suppresses the checkpoint function of p53 and thus promotes genome instability in cells expressing the CCNE1 oncogene.
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- $a Oncogene-induced replication stress has been recognized as a major cause of genome instability in cancer cells. Increased expression of cyclin E1 caused by amplification of the CCNE1 gene is a common cause of replication stress in various cancers. Protein phosphatase magnesium-dependent 1 delta (PPM1D) is a negative regulator of p53 and has been implicated in termination of the cell cycle checkpoint. Amplification of the PPM1D gene or frameshift mutations in its final exon promote tumorigenesis. Here, we show that PPM1D activity further increases the replication stress caused by overexpression of cyclin E1. In particular, we demonstrate that cells expressing a truncated mutant of PPM1D progress faster from G1 to S phase and fail to complete licensing of the replication origins. In addition, we show that transcription-replication collisions and replication fork slowing caused by CCNE1 overexpression are exaggerated in cells expressing the truncated PPM1D. Finally, replication speed and accumulation of focal DNA copy number alterations caused by induction of CCNE1 expression was rescued by pharmacological inhibition of PPM1D. We propose that increased activity of PPM1D suppresses the checkpoint function of p53 and thus promotes genome instability in cells expressing the CCNE1 oncogene.
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