{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:00:12Z","timestamp":1785420012226,"version":"3.56.0"},"posted":{"date-parts":[[2025,11,6]]},"group-title":"Cell Biology","reference-count":41,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T00:00:00Z","timestamp":1762387200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"award":["T32GM136577"],"award-info":[{"award-number":["T32GM136577"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"award":["NRF-MSG-2023-0001"],"award-info":[{"award-number":["NRF-MSG-2023-0001"]}],"id":[{"id":"https:\/\/ror.org\/03cpyc314","id-type":"ROR","asserted-by":"publisher"}]},{"award":["FDN-167277"],"award-info":[{"award-number":["FDN-167277"]}],"id":[{"id":"https:\/\/ror.org\/01gavpb45","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,12,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Aneuploidy is a hallmark of cancer and is a potential vulnerability that can be selectively targeted. To systematically identify genes that affect the incidence and fitness of aneuploid cells, we conducted a genome-wide CRISPR\/Cas9 screen using NMS-P715, an inhibitor of the spindle assembly checkpoint (SAC) kinase MPS1\/TTK. In this study, we identified a number of genes known to regulate aneuploidy and mitosis, and subsequently focused on\n                  <jats:italic>PRR14L<\/jats:italic>\n                  , a ubiquitously expressed gene previously implicated in chronic myelomonocytic leukemia (CMML). Proximity labeling of PRR14L using TurboID revealed several cell division proteins, including the PP2A-B56 phosphatase complex and the spindle assembly factor TACC3, as PRR14L-interacting proteins. Loss of PRR14L prolongs SAC-dependent mitotic arrest in response to microtubule depolymerization but, paradoxically, leads to catastrophic mitotic errors upon SAC abrogation by MPS1 inhibitors. A model derived from our findings provides a rationale for exploiting MPS1 inhibition as a potential vulnerability in cancers containing either PRR14L loss of function mutations or FGFR-TACC3 fusions.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Significance Statement<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>Aneuploidy is a hallmark of cancer. Whether aneuploidy can be selectively targeted is not known.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Utilizing a CRISPR\/Cas9 screen, the authors found that loss of the gene PRR14L sensitizes cells to aneuploidy induction. Taking advantage of live cell imaging and proximity labeling, they linked PRR14L to TACC3 and mitosis.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>These findings suggest that spindle checkpoint inhibitors may have therapeutic potential in cancers with either loss-of-function PRR14L and\/or gain of function TACC3 mutations.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.1101\/2025.11.04.686150","type":"posted-content","created":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T20:20:24Z","timestamp":1762460424000},"source":"Crossref","is-referenced-by-count":0,"title":["The scaffold protein PRR14L links the PP2A-TACC3 axis to mitotic fidelity and sensitivity to MPS1 inhibition"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9387-0878","authenticated-orcid":false,"given":"Albert Z.","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Cell Biology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA"},{"name":"Mechanobiology Institute, National University of Singapore, Singapore 117411, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3649-1230","authenticated-orcid":false,"given":"Akshay","family":"Narkar","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-4174-8855","authenticated-orcid":false,"given":"Keming","family":"Li","sequence":"additional","affiliation":[{"name":"Mechanobiology Institute, National University of Singapore, Singapore 117411, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5313-7057","authenticated-orcid":false,"given":"Thierry","family":"Bertomeu","sequence":"additional","affiliation":[{"name":"The ChemoGenix CRISPR screening facility of the Institute for Research in Immunology and Cancer, University of Montreal, 2950 Chemin de Polytechnique, Montr\u00e9al, QC H3T 1J4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7830-2453","authenticated-orcid":false,"given":"Blake A.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0292-7654","authenticated-orcid":false,"given":"Jasmin","family":"Coulombe-Huntington","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, McGill University, Montreal, QC H3A 0E9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9802-4953","authenticated-orcid":false,"given":"Yi","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Zhu","sequence":"additional","affiliation":[{"name":"Mechanobiology Institute, National University of Singapore, Singapore 117411, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9713-9994","authenticated-orcid":false,"given":"Mike","family":"Tyers","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, University of Toronto; Toronto, Ontario M5S 1A8, Canada"},{"name":"Program in Molecular Medicine, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0540-6566","authenticated-orcid":false,"given":"Rong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA"},{"name":"Mechanobiology Institute, National University of Singapore, Singapore 117411, Singapore"},{"name":"Department of Biological Sciences, National University of Singapore, Singapore 117558, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026010202300729000_2025.11.04.686150v2.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-023-02085-6"},{"key":"2026010202300729000_2025.11.04.686150v2.2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1382"},{"key":"2026010202300729000_2025.11.04.686150v2.3","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1038\/s43018-023-00711-y","article-title":"Aneuploidy and complex genomic rearrangements in cancer evolution","volume":"5","year":"2024","journal-title":"Nat Cancer"},{"key":"2026010202300729000_2025.11.04.686150v2.4","doi-asserted-by":"crossref","unstructured":"Bakhoum, SF , and Landau, DA (2017). Chromosomal instability as a driver of tumor heterogeneity and evolution. Cold Spring Harb Perspect Med 7.","DOI":"10.1101\/cshperspect.a029611"},{"key":"2026010202300729000_2025.11.04.686150v2.5","doi-asserted-by":"publisher","DOI":"10.1038\/nature25432"},{"key":"2026010202300729000_2025.11.04.686150v2.6","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00186-18"},{"key":"2026010202300729000_2025.11.04.686150v2.7","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2011.15"},{"key":"2026010202300729000_2025.11.04.686150v2.8","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.4201"},{"key":"2026010202300729000_2025.11.04.686150v2.9","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-14-1337"},{"key":"2026010202300729000_2025.11.04.686150v2.10","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.gore.2015.06.005","article-title":"FGFR3-TACC3: A novel gene fusion in cervical cancer","volume":"13","year":"2015","journal-title":"Gynecol Oncol Rep"},{"key":"2026010202300729000_2025.11.04.686150v2.11","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-018-0340-5"},{"key":"2026010202300729000_2025.11.04.686150v2.12","doi-asserted-by":"crossref","unstructured":"Chase, A , Tarragona, GC , Lin, F , Yapp, S , Score, J , Bryant, C , and Cross, NCP (2023). Identification of B56 \u03b1 , B56 \u03b3 and BAP1 as PRR14L binding partners. 1\u201315.","DOI":"10.1101\/2023.04.29.538809"},{"key":"2026010202300729000_2025.11.04.686150v2.13","doi-asserted-by":"publisher","DOI":"10.1038\/s41596-020-0399-0"},{"key":"2026010202300729000_2025.11.04.686150v2.14","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-10-2101"},{"key":"2026010202300729000_2025.11.04.686150v2.15","doi-asserted-by":"publisher","DOI":"10.1089\/crispr.2021.0113"},{"key":"2026010202300729000_2025.11.04.686150v2.16","doi-asserted-by":"crossref","unstructured":"Dobles, M , Liberal, V , Scott, ML , Benezra, R , and Sorger, PK (2000). Chromosome Missegregation and Apoptosis in Mice Lacking the Mitotic Checkpoint Protein Mad2, Li and Nicklas.","DOI":"10.1016\/S0092-8674(00)80875-2"},{"key":"2026010202300729000_2025.11.04.686150v2.17","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.1318"},{"key":"2026010202300729000_2025.11.04.686150v2.18","doi-asserted-by":"crossref","unstructured":"Gill, KP , and Denham, M (2020). Optimized Transgene Delivery Using Third-Generation Lentiviruses. Curr Protoc Mol Biol 133.","DOI":"10.1002\/cpmb.125"},{"key":"2026010202300729000_2025.11.04.686150v2.19","doi-asserted-by":"publisher","DOI":"10.1038\/nrg3123"},{"key":"2026010202300729000_2025.11.04.686150v2.20","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201002133"},{"key":"2026010202300729000_2025.11.04.686150v2.21","doi-asserted-by":"crossref","unstructured":"Johnson, BA , Liu, AZ , Bi, T , Dong, Y , Li, T , Zhou, D , Narkar, A , Wu, Y , Sun, SX , Larman, TC , et al. (2024). Simple aneuploidy evades p53 surveillance and promotes niche factor-independent growth in human intestinal organoids. Mol Biol Cell.","DOI":"10.1091\/mbc.E24-04-0166"},{"key":"2026010202300729000_2025.11.04.686150v2.22","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E17-01-0051"},{"key":"2026010202300729000_2025.11.04.686150v2.23","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.195164"},{"key":"2026010202300729000_2025.11.04.686150v2.24","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2021.06.009"},{"key":"2026010202300729000_2025.11.04.686150v2.25","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200911120"},{"key":"2026010202300729000_2025.11.04.686150v2.26","doi-asserted-by":"crossref","first-page":"108892","DOI":"10.1016\/j.celrep.2021.108892","article-title":"On the role of p53 in the cellular response to aneuploidy","volume":"34","year":"2021","journal-title":"Cell Rep"},{"key":"2026010202300729000_2025.11.04.686150v2.27","doi-asserted-by":"crossref","unstructured":"Normandin, K , Coulombe-Huntington, J , St-Denis, C , Bernard, A , Bourouh, M , Bertomeu, T , Tyers, M , and Archambault, V (2023). Genetic enhancers of partial PLK1 inhibition reveal hypersensitivity to kinetochore perturbations. PLoS Genet 19.","DOI":"10.1371\/journal.pgen.1010903"},{"key":"2026010202300729000_2025.11.04.686150v2.28","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.194662"},{"key":"2026010202300729000_2025.11.04.686150v2.29","doi-asserted-by":"crossref","unstructured":"Replogle, JM , Zhou, W , Amaro, AE , Mcfarland, JM , Villalobos-Ortiz, M , Ryan, J , Letai, A , Yilmaz, O , Sheltzer, J , Lippard, SJ , et al. (2020). Aneuploidy increases resistance to chemotherapeutics by antagonizing cell division.","DOI":"10.1073\/pnas.2009506117"},{"key":"2026010202300729000_2025.11.04.686150v2.30","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3047"},{"key":"2026010202300729000_2025.11.04.686150v2.31","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-16-0645"},{"key":"2026010202300729000_2025.11.04.686150v2.32","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201001036"},{"key":"2026010202300729000_2025.11.04.686150v2.33","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2089"},{"key":"2026010202300729000_2025.11.04.686150v2.34","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2781"},{"key":"2026010202300729000_2025.11.04.686150v2.35","doi-asserted-by":"publisher","DOI":"10.1126\/science.1220834"},{"key":"2026010202300729000_2025.11.04.686150v2.36","doi-asserted-by":"crossref","unstructured":"Smela, MDP , Kramme, CC , Fortuna, PRJ , Adams, JL , Su, R , Dong, E , Kobayashi, M , Brixi, G , Kavirayuni, VS , Tysinger, E , et al. (2023). Directed differentiation of human iPSCs to functional ovarian granulosa-like cells via transcription factor overexpression. Elife 12.","DOI":"10.7554\/eLife.87987"},{"key":"2026010202300729000_2025.11.04.686150v2.37","doi-asserted-by":"crossref","unstructured":"Still, IH , Vince, P , and Cowell, JK (1999). The Third Member of the Transforming Acidic Coiled Coil-Containing Gene Family, TACC3, Maps in 4p16, Close to Translocation Breakpoints in Multiple Myeloma, and Is Upregulated in Various Cancer Cell Lines.","DOI":"10.1006\/geno.1999.5829"},{"key":"2026010202300729000_2025.11.04.686150v2.38","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200712029"},{"key":"2026010202300729000_2025.11.04.686150v2.39","doi-asserted-by":"publisher","DOI":"10.7554\/elife.39324"},{"key":"2026010202300729000_2025.11.04.686150v2.40","doi-asserted-by":"crossref","unstructured":"Wickham, H (2016). ggplot2 Elegant Graphics for Data Analysis Second Edition, Houston.","DOI":"10.1007\/978-3-319-24277-4_9"},{"key":"2026010202300729000_2025.11.04.686150v2.41","doi-asserted-by":"crossref","unstructured":"Wong, S-S , Monteiro, JM , Chang, C-C , Peng, M , Mohamed, N , Steinacker, TL , Xiao, B , Saurya, S , Wainman, A , and Raff, JW (2025). Centrioles generate two scaffolds with distinct biophysical properties to build mitotic centrosomes. Sci Adv.","DOI":"10.1101\/2024.04.09.588708"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.11.04.686150","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T09:58:26Z","timestamp":1768471106000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.11.04.686150"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,6]]},"references-count":41,"URL":"https:\/\/doi.org\/10.1101\/2025.11.04.686150","relation":{},"subject":[],"published":{"date-parts":[[2025,11,6]]},"subtype":"preprint"}}