Pavani, M. and Bonaiuti, P. and Chiroli, E. and Gross, F. and Natali, F. and Póti, Ádám and Farkas, Zoltán and Szüts, Dávid (2021) Epistasis, aneuploidy, and functional mutations underlie evolution of resistance to induced microtubule depolymerization. EMBO JOURNAL, 40 (22). ISSN 0261-4189
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Abstract
Cells with blocked microtubule polymerization are delayed in mitosis, but eventually manage to proliferate despite substantial chromosome missegregation. While several studies have analyzed the first cell division after microtubule depolymerization, we have asked how cells cope long-term with microtubule impairment. We allowed 24 clonal populations of yeast cells with beta-tubulin mutations preventing proper microtubule polymerization, to evolve for ˜150 generations. At the end of the laboratory evolution experiment, cells had regained the ability to form microtubules and were less sensitive to microtubule-depolymerizing drugs. Whole-genome sequencing identified recurrently mutated genes, in particular for tubulins and kinesins, as well as pervasive duplication of chromosome VIII. Recreating these mutations and chromosome VIII disomy prior to evolution confirmed that they allow cells to compensate for the original mutation in beta-tubulin. Most of the identified mutations did not abolish function, but rather restored microtubule functionality. Analysis of the temporal order of resistance development in independent populations repeatedly revealed the same series of events: disomy of chromosome VIII followed by a single additional adaptive mutation in either tubulins or kinesins. Since tubulins are highly conserved among eukaryotes, our results have implications for understanding resistance to microtubule-targeting drugs widely used in cancer therapy. © 2021 IFOM – the FIRC Institute of Molecular Oncology
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| Additional Information: | IFOM, The Firc Institute of Molecular Oncology, Milano, Italy Institute of Medical Biology (IMB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary IEO, European Institute of Oncology IRCCS, Milan, Italy Human Technopole, Milano, Italy Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre, Szeged, Hungary Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche (IGM-CNR), Pavia, Italy Export Date: 11 October 2021 CODEN: EMJOD Correspondence Address: Ciliberto, A.; IFOM, Italy; email: andrea.ciliberto@ifom.eu Funding details: AIRC‐IG 23258, UNKP‐20‐5‐SZTE‐646, UNKP‐21‐5‐SZTE‐562 Funding details: FIEK_16‐1‐2016‐0005, K_124881, NRF‐NRFI05‐2019‐0008 Funding details: Ministero della Salute Funding details: Magyar Tudományos Akadémia, MTA, BO/779/20 Funding details: Fondazione Umberto Veronesi Funding details: Associazione Italiana per la Ricerca sul Cancro, AIRC, AIRC‐IG 21556 Funding details: Nemzeti Kutatási Fejlesztési és Innovációs Hivatal, NKFIH, FK 128775 Funding text 1: This paper is dedicated to John J. Tyson, mentor and friend, on the occasion of his retirement. We thank Silke Hauf, Claudio Vernieri, and Andrea Musacchio for constructive comments on the manuscript. Camilla Cancrini helped us in the final stages of this work. We thank Marco Foiani, Michael Knop, Roberta Fraschini, Simonetta Piatti, and Tim Huffaker for sharing reagents with us. Work in the group of AC is financed by AIRC, the Italian association for cancer research (Grant AIRC‐IG 21556); MP benefits of a AIRC fellowship; SeP receives supports from the Italian Ministry of Health (Ricerca Corrente and 5x1000 funds); SiP benefits from a Fondazione Umberto Veronesi fellowship; ZF is supported by the National Research, Development and Innovation Office of Hungary (FK 128775), a Janos Bolyai Research Fellowship from the Hungarian Academy of Sciences (BO/779/20) and the New National Excellence Program of the Hungarian Ministry of Human Capacities (Bolyai+, UNKP‐20‐5‐SZTE‐646 and UNKP‐21‐5‐SZTE‐562); the group of MCL is supported by AIRC, the Italian association for cancer research (Grant AIRC‐IG 23258); DS lab is supported by the National Research, Development and Innovation Fund of Hungary (grants K_124881 and FIEK_16‐1‐2016‐0005); GR lab is supported by a Singapore NRF Investigatorship (NRF‐NRFI05‐2019‐0008); the Hungarian Academy of Sciences sponsored the collaboration between the groups of AC and DS by awarding a visiting fellowship to AC. |
| Uncontrolled Keywords: | CHROMOSOME SEGREGATION; laboratory evolution; microtubule dynamics; resistance to antimitotics; |
| Subjects: | Q Science / természettudomány > QH Natural history / természetrajz > QH301 Biology / biológia > QH3011 Biochemistry / biokémia Q Science / természettudomány > QH Natural history / természetrajz > QH426 Genetics / genetika, örökléstan |
| SWORD Depositor: | MTMT SWORD |
| Depositing User: | MTMT SWORD |
| Date Deposited: | 07 Feb 2022 14:56 |
| Last Modified: | 07 Feb 2022 14:56 |
| URI: | http://real.mtak.hu/id/eprint/137535 |
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