Topoisomerase 1 activity during mitotic transcription favors the transition from mitosis to G1
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- Topoisomerase 1 activity during mitotic transcription favors the transition from mitosis to G1
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As cells enter mitosis, chromatin compacts to facilitate chromosome segregation yet remains transcribed. Transcription supercoils DNA to levels that can impede further progression of RNA polymerase II (RNAPII) unless it is removed by DNA topoisomerase 1 (TOP1). Using ChIP-seq on mitotic cells, we found that TOP1 is required for RNAPII translocation along genes. The stimulation of TOP1 activity by RNAPII during elongation allowed RNAPII clearance from genes in prometaphase and enabled chromosomal segregation. Disruption of the TOP1-RNAPII interaction impaired RNAPII spiking at promoters and triggered defects in the post-mitotic transcription program. This program includes factors necessary for cell growth, and cells with impaired TOP1-RNAPII interaction are more sensitive to inhibitors of mTOR signaling. We conclude that TOP1 is necessary for assisting transcription during mitosis with consequences for growth and gene expression long after mitosis is completed. In this sense, TOP1 ensures that cellular memory is preserved in subsequent generations.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Molecular Cell |
| Vol/bind | 81 |
| Udgave nummer | 24 |
| Sider (fra-til) | 5007-5024.e9 |
| ISSN | 1097-2765 |
| DOI | |
| Status | Udgivet - 2021 |
Bibliografisk note
Funding Information:
This work was supported by grants from the Wallenberg Foundation (WAF in Medicine 2016), the Swedish Research Council (2016-02610 VR), the Swedish Governmental Agency for Innovation Systems (2016-02055 VINNOVA), Karolinska Institutet (KID grants 2018), and Cancerfonden (180608) to L.B.; by a grant from Japan Society for the Promotion of Science (JSPS) KAKENHI (grant JP19K06495) to T.N.; and by grants from the Swedish Research Council, the Ragnar S?derberg Foundation (Fellows in Medicine 2016), and Karolinska Institutet (KID grants 2017) to N.C. We thank Dr. Levens and Dr. Bj?rkegren for helpful advice and critical discussion, Dr. Kuznetsova for valuable feedback and reagents, Ms. Busquet for help with some experiments, and Dr. Kutter and Mr. Atanasoai for technical expertise. The computations and data storage were enabled by resources in project (SNIC 2018/8-390) provided by the Swedish National Infrastructure for Computing (SNIC) at UPPMAX, partially funded by the Swedish Research Council through grant agreement 2018-05973. Cell imaging was performed at the Biomedicum Imaging Core (BIC) with support from Karolinska Institutet. We acknowledge the Biomedicum Flow Cytometry Core Facility (Karolinska Institutet), supported by KI/SLL, for technical expertise. The graphical abstract was created using BioRender.com. Conceptualization, L.B. A.W. V.K. D.P.C. and A.L.; Methodology, L.B. A.W. V.K. D.P.C. I.K. and A.H.B.; Software, V.K. J.G. and R.M.; Investigation, L.B. A.W. V.K. D.P.C. M.C. R.G. R.B. F.V. A.H.B. and I.K.; Resources, T.N. and N.C.; Writing ? Original Draft, L.B. A.W. V.K. and D.P.C.; Writing ? Review & Editing, L.B. A.L. N.C. F.K. D.P.C. A.W. V.K. and A.H.B.; Visualization, A.W. V.K. D.P.C. J.G. R.M. and I.K.; Supervision, L.B. N.C. and F.K.; Funding Acquisition, L.B. N.C. and T.N. The authors declare no competing interests. While citing references scientifically relevant for this work, we also actively worked to promote gender balance in our reference list.
Funding Information:
This work was supported by grants from the Wallenberg Foundation ( WAF in Medicine 2016 ), the Swedish Research Council ( 2016-02610 VR ), the Swedish Governmental Agency for Innovation Systems ( 2016-02055 VINNOVA ), Karolinska Institutet (KID grants 2018), and Cancerfonden ( 180608 ) to L.B.; by a grant from Japan Society for the Promotion of Science (JSPS) KAKENHI (grant JP19K06495 ) to T.N.; and by grants from the Swedish Research Council , the Ragnar Söderberg Foundation (Fellows in Medicine 2016), and Karolinska Institutet (KID grants 2017) to N.C. We thank Dr. Levens and Dr. Björkegren for helpful advice and critical discussion, Dr. Kuznetsova for valuable feedback and reagents, Ms. Busquet for help with some experiments, and Dr. Kutter and Mr. Atanasoai for technical expertise. The computations and data storage were enabled by resources in project (SNIC 2018/8-390) provided by the Swedish National Infrastructure for Computing (SNIC) at UPPMAX, partially funded by the Swedish Research Council through grant agreement 2018-05973 . Cell imaging was performed at the Biomedicum Imaging Core (BIC) with support from Karolinska Institutet . We acknowledge the Biomedicum Flow Cytometry Core Facility (Karolinska Institutet), supported by KI/SLL , for technical expertise. The graphical abstract was created using BioRender.com .
Publisher Copyright:
© 2021 The Authors
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