PT - JOURNAL ARTICLE AU - Suganthi Chittaranjan AU - Jungeun Song AU - Susanna Y. Chan AU - Stephen Dongsoo Lee AU - Shiekh Tanveer Ahmad AU - William Brothers AU - Richard D. Corbett AU - Alessia Gagliardi AU - Amy Lum AU - Annie Moradian AU - Stephen Pleasance AU - Robin Coope AU - J Gregory Cairncross AU - Stephen Yip AU - Emma Laks AU - Samuel A.J.R. Aparicio AU - Jennifer A. Chan AU - Christopher S. Hughes AU - Gregg B. Morin AU - Veronique G. LeBlanc AU - Marco A. Marra TI - Loss of CIC promotes mitotic dysregulation and chromosome segregation defects AID - 10.1101/533323 DP - 2019 Jan 01 TA - bioRxiv PG - 533323 4099 - http://biorxiv.org/content/early/2019/01/29/533323.short 4100 - http://biorxiv.org/content/early/2019/01/29/533323.full AB - Background CIC is a transcriptional repressor inactivated by loss-of-function mutations in several cancer types, including gliomas, lung cancers, and gastric adenocarcinomas. CIC alterations and/or loss of CIC activity have been associated with poorer outcomes and more aggressive phenotypes across cancer types, which is consistent with the notion that CIC functions as a tumour suppressor across a wide range of contexts.Results Using mammalian cells lacking functional CIC, we found that CIC deficiency was associated with chromosome segregation (CS) defects, resulting in chromosomal instability and aneuploidy. These CS defects were associated with transcriptional dysregulation of spindle assembly checkpoint and cell cycle regulators. We also identified novel CIC interacting proteins, including core members of the SWI/SNF complex, and showed that they cooperatively regulated the expression of genes involved in cell cycle regulation. Finally, we showed that loss of CIC and ARID1A cooperatively increased CS defects and reduced cell viability.Conclusions Our study ascribes a novel role to CIC as an important regulator of the cell cycle and demonstrates that loss of CIC can lead to chromosomal instability and aneuploidy in human and murine cells through defects in CS, providing insight into the underlying mechanisms of CIC’s increasingly apparent role as a “pan-cancer” tumour suppressor.