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Efficient Pre-mRNA Cleavage Prevents Replication-Stress-Associated Genome Instability
F. Teloni, J. Michelena, A. Lezaja, S. Kilic, C. Ambrosi, S. Menon, J. Dobrovolna, R. Imhof, P. Janscak, T. Baubec, M. Altmeyer,
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články, práce podpořená grantem
NLK
Cell Press Free Archives
od 1997-12-01 do Před 1 rokem
Free Medical Journals
od 1997 do Před 1 rokem
Free Medical Journals
od 1997 do Před 1 rokem
Open Access Digital Library
od 1997-12-01
- MeSH
- aktivní transport - buněčné jádro MeSH
- DNA nádorová genetika metabolismus MeSH
- HeLa buňky MeSH
- heteroduplexy nukleové kyseliny genetika metabolismus MeSH
- jaderné proteiny genetika metabolismus MeSH
- lidé MeSH
- messenger RNA biosyntéza genetika MeSH
- nádory genetika metabolismus MeSH
- nestabilita genomu * MeSH
- polyadenylace MeSH
- poškození DNA * MeSH
- prekurzory RNA biosyntéza genetika MeSH
- proteiny buněčného cyklu genetika metabolismus MeSH
- regulace genové exprese u nádorů MeSH
- replikace DNA * MeSH
- RNA nádorová biosyntéza genetika MeSH
- štěpení RNA * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Cellular mechanisms that safeguard genome integrity are often subverted in cancer. To identify cancer-related genome caretakers, we employed a convergent multi-screening strategy coupled to quantitative image-based cytometry and ranked candidate genes according to multivariate readouts reflecting viability, proliferative capacity, replisome integrity, and DNA damage signaling. This unveiled regulators of replication stress resilience, including components of the pre-mRNA cleavage and polyadenylation complex. We show that deregulation of pre-mRNA cleavage impairs replication fork speed and leads to excessive origin activity, rendering cells highly dependent on ATR function. While excessive formation of RNA:DNA hybrids under these conditions was tightly associated with replication-stress-induced DNA damage, inhibition of transcription rescued fork speed, origin activation, and alleviated replication catastrophe. Uncoupling of pre-mRNA cleavage from co-transcriptional processing and export also protected cells from replication-stress-associated DNA damage, suggesting that pre-mRNA cleavage provides a mechanism to efficiently release nascent transcripts and thereby prevent gene gating-associated genomic instability.
Department of Molecular Mechanisms of Disease University of Zurich 8057 Zurich Switzerland
Institute of Molecular Cancer Research University of Zurich 8057 Zurich Switzerland
Citace poskytuje Crossref.org
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