-
Something wrong with this record ?
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,
Language English Country United States
Document type Journal Article, Research Support, Non-U.S. Gov't
NLK
Cell Press Free Archives
from 1997-12-01 to 1 year ago
Free Medical Journals
from 1997 to 1 year ago
Free Medical Journals
from 1997 to 1 year ago
Open Access Digital Library
from 1997-12-01
- MeSH
- Active Transport, Cell Nucleus MeSH
- DNA, Neoplasm genetics metabolism MeSH
- HeLa Cells MeSH
- Nucleic Acid Heteroduplexes genetics metabolism MeSH
- Nuclear Proteins genetics metabolism MeSH
- Humans MeSH
- RNA, Messenger biosynthesis genetics MeSH
- Neoplasms genetics metabolism MeSH
- Genomic Instability * MeSH
- Polyadenylation MeSH
- DNA Damage * MeSH
- RNA Precursors biosynthesis genetics MeSH
- Cell Cycle Proteins genetics metabolism MeSH
- Gene Expression Regulation, Neoplastic MeSH
- DNA Replication * MeSH
- RNA, Neoplasm biosynthesis genetics MeSH
- RNA Cleavage * MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't 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
References provided by Crossref.org
- 000
- 00000naa a2200000 a 4500
- 001
- bmc19027913
- 003
- CZ-PrNML
- 005
- 20190823102431.0
- 007
- ta
- 008
- 190813s2019 xxu f 000 0|eng||
- 009
- AR
- 024 7_
- $a 10.1016/j.molcel.2018.11.036 $2 doi
- 035 __
- $a (PubMed)30639241
- 040 __
- $a ABA008 $b cze $d ABA008 $e AACR2
- 041 0_
- $a eng
- 044 __
- $a xxu
- 100 1_
- $a Teloni, Federico $u Department of Molecular Mechanisms of Disease, University of Zurich, 8057 Zurich, Switzerland; Life Science Zurich Graduate School (LSZGS), 8057 Zurich, Switzerland.
- 245 10
- $a Efficient Pre-mRNA Cleavage Prevents Replication-Stress-Associated Genome Instability / $c F. Teloni, J. Michelena, A. Lezaja, S. Kilic, C. Ambrosi, S. Menon, J. Dobrovolna, R. Imhof, P. Janscak, T. Baubec, M. Altmeyer,
- 520 9_
- $a 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.
- 650 _2
- $a aktivní transport - buněčné jádro $7 D021581
- 650 _2
- $a proteiny buněčného cyklu $x genetika $x metabolismus $7 D018797
- 650 12
- $a poškození DNA $7 D004249
- 650 12
- $a replikace DNA $7 D004261
- 650 _2
- $a DNA nádorová $x genetika $x metabolismus $7 D004273
- 650 _2
- $a regulace genové exprese u nádorů $7 D015972
- 650 12
- $a nestabilita genomu $7 D042822
- 650 _2
- $a HeLa buňky $7 D006367
- 650 _2
- $a lidé $7 D006801
- 650 _2
- $a nádory $x genetika $x metabolismus $7 D009369
- 650 _2
- $a jaderné proteiny $x genetika $x metabolismus $7 D009687
- 650 _2
- $a heteroduplexy nukleové kyseliny $x genetika $x metabolismus $7 D009692
- 650 _2
- $a polyadenylace $7 D026723
- 650 12
- $a štěpení RNA $7 D059367
- 650 _2
- $a prekurzory RNA $x biosyntéza $x genetika $7 D012322
- 650 _2
- $a messenger RNA $x biosyntéza $x genetika $7 D012333
- 650 _2
- $a RNA nádorová $x biosyntéza $x genetika $7 D012334
- 655 _2
- $a časopisecké články $7 D016428
- 655 _2
- $a práce podpořená grantem $7 D013485
- 700 1_
- $a Michelena, Jone $u Department of Molecular Mechanisms of Disease, University of Zurich, 8057 Zurich, Switzerland.
- 700 1_
- $a Lezaja, Aleksandra $u Department of Molecular Mechanisms of Disease, University of Zurich, 8057 Zurich, Switzerland; Life Science Zurich Graduate School (LSZGS), 8057 Zurich, Switzerland.
- 700 1_
- $a Kilic, Sinan $u Department of Molecular Mechanisms of Disease, University of Zurich, 8057 Zurich, Switzerland.
- 700 1_
- $a Ambrosi, Christina $u Department of Molecular Mechanisms of Disease, University of Zurich, 8057 Zurich, Switzerland; Life Science Zurich Graduate School (LSZGS), 8057 Zurich, Switzerland.
- 700 1_
- $a Menon, Shruti $u Institute of Molecular Cancer Research, University of Zurich, 8057 Zurich, Switzerland; Life Science Zurich Graduate School (LSZGS), 8057 Zurich, Switzerland.
- 700 1_
- $a Dobrovolna, Jana $u Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Videnska 1083, 143 00 Czech Republic.
- 700 1_
- $a Imhof, Ralph $u Department of Molecular Mechanisms of Disease, University of Zurich, 8057 Zurich, Switzerland.
- 700 1_
- $a Janscak, Pavel $u Institute of Molecular Cancer Research, University of Zurich, 8057 Zurich, Switzerland; Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Videnska 1083, 143 00 Czech Republic.
- 700 1_
- $a Baubec, Tuncay $u Department of Molecular Mechanisms of Disease, University of Zurich, 8057 Zurich, Switzerland.
- 700 1_
- $a Altmeyer, Matthias $u Department of Molecular Mechanisms of Disease, University of Zurich, 8057 Zurich, Switzerland. Electronic address: matthias.altmeyer@uzh.ch.
- 773 0_
- $w MED00011398 $t Molecular cell $x 1097-4164 $g Roč. 73, č. 4 (2019), s. 670-683.e12
- 856 41
- $u https://pubmed.ncbi.nlm.nih.gov/30639241 $y Pubmed
- 910 __
- $a ABA008 $b sig $c sign $y a $z 0
- 990 __
- $a 20190813 $b ABA008
- 991 __
- $a 20190823102645 $b ABA008
- 999 __
- $a ok $b bmc $g 1433062 $s 1066373
- BAS __
- $a 3
- BAS __
- $a PreBMC
- BMC __
- $a 2019 $b 73 $c 4 $d 670-683.e12 $e 20190110 $i 1097-4164 $m Molecular cell $n Mol Cell $x MED00011398
- LZP __
- $a Pubmed-20190813
