Topoisomerase 1 activity during mitotic transcription favors the transition from mitosis to G1

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 fo...

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Veröffentlicht in:Molecular cell 2021-12, Vol.81 (24), p.5007-5024.e9
Hauptverfasser: Wiegard, Anika, Kuzin, Vladislav, Cameron, Donald P., Grosser, Jan, Ceribelli, Michele, Mehmood, Rashid, Ballarino, Roberto, Valant, Francesco, Grochowski, Radosław, Karabogdan, Ivana, Crosetto, Nicola, Lindqvist, Arne, Bizard, Anna Helene, Kouzine, Fedor, Natsume, Toyoaki, Baranello, Laura
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Sprache:eng
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Zusammenfassung: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. [Display omitted] •TOP1 promotes RNAPII transcription and clearance from chromosomes in prometaphase•TOP1 assists RNAPII promoter loading during mitotic exit to restart transcription•Loss of TOP1-RNAPII interaction causes supercoil buildup and segregation defects•Disrupting TOP1-RNAPII binding affects growth and sensitizes cells to mTOR drugs Wiegard et al. demonstrate that TOP1 assists RNAPII during mitotic transcription. TOP1-RNAPII interaction facilitates completion of transcription during prometaphase and reloading of RNAPII at promoters during mitotic exit, thus favoring progression into G1. Interfering with TOP1-RNAPII interaction affects the transcriptional program of the cell and the progression through cell cycle.
ISSN:1097-2765
1097-4164
1097-4164
DOI:10.1016/j.molcel.2021.10.015