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Loss of CIC promotes mitotic dysregulation and chromosome segregation defects

Chittaranjan, Suganthi and Song, Jungeun and Chan, Susanna Y. and Lee, Stephen Dongsoo and Tanveer Ahmad, Shiekh and Brothers, William and Corbett, Richard D. and Gagliardi, Alessia and Lum, Amy and Moradian, Annie and Pleasance, Stephen and Coope, Robin and Cairncross, J. Gregory and Yip, Stephen and Laks, Emma and Aparicio, Samuel A. J. R. and Chan, Jennifer A. and Hughes, Chistopher S. and Morin, Gregg B. and LeBlanc, Veronique G. and Marra, Marco A. (2019) Loss of CIC promotes mitotic dysregulation and chromosome segregation defects. . (Unpublished) http://resolver.caltech.edu/CaltechAUTHORS:20190130-162009811

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Abstract

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.


Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription
https://doi.org/10.1101/533323DOIDiscussion Paper
https://www.biorxiv.org/content/10.1101/533323v1.supplementary-materialPublisherSupporting Information
ORCID:
AuthorORCID
Moradian, Annie0000-0002-0407-2031
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. We thank the DNA sequencing, library construction, and biospecimen core facilities at the BC Cancer Genome Sciences Centre for technical support. We thank Robyn Roscoe and Joanne Johnson for expert Project Management support. The authors thank Diane Trinh for helpful edits and comments on the manuscript and Dr. G. Dawson (The University of Chicago, Illinois, USA) for providing the HOG glioma cell line. MAM acknowledges the support of the Canadian Institutes of Health Research (FDN-143288); the Canada Research Chairs program and the BC Cancer Foundation (BCCF), and is especially grateful to Ms. Donna Anderson for her generosity in supporting this project. GBM acknowledges support from the BC Cancer Foundation. Author contributions: MAM and SC conceived and designed experiments. JS, SYC and SC produced the reagents and tools required for the in vitro experiments. STA and JAC provided the mice brain material. JS, SYC, SDL, AL, AG, and SC performed most experiments. AM, CSH, and GBM performed and/or advised on the mass spectrometry experiments and CSH and SC analyzed the data. SA, SP, RC, and EL performed and/or advised on the DLP+ experiments, and RDC and VL analyzed and interpreted the data. AL and SY performed the FISH experiments, and AL and SC analyzed the data. SC wrote initial drafts and MAM and VL edited the manuscript. JAC, SAA, GBM, GJC, and SY provided ideas, discussion and edits to the manuscript. MAM provided oversight. Data availability: The data that support the findings in this study are available from the corresponding author upon reasonable request. Ethics statement: Animal use was approved by the University of Calgary Animal Care Committee (protocol AC16-0266) in compliance with the Guidelines of the Canadian Council of Animal Care. Competing interests statement: SY is on the advisory boards of Bayer AG and Pfizer Inc., and has received travel support from Foundation Medicine Inc. SAA is a co-founder of and consultant to Contextual Genomics Ltd and is on the advisory boards of Sangamo Biosciences and Repare Therapeutics. The remaining authors declare no competing interests.
Funders:
Funding AgencyGrant Number
Canadian Institutes of Health Research (CIHR)FDN-143288
Canada Research Chairs ProgramUNSPECIFIED
BC Cancer FoundationUNSPECIFIED
Subject Keywords:CIC, SWI/SNF complex, tumour suppressor, spindle assembly checkpoint, cell cycle, chromosome segregation, aneuploidy, transcription, cancer
Record Number:CaltechAUTHORS:20190130-162009811
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20190130-162009811
Official Citation:Loss of CIC promotes mitotic dysregulation and chromosome segregation defects Suganthi Chittaranjan, Jungeun Song, Susanna Y Chan, Stephen Dongsoo Lee, Shiekh Tanveer Ahmad, William Brothers, Richard D Corbett, Alessia Gagliardi, Amy Lum, Annie Moradian, Stephen Pleasance, Robin Coope, J Gregory Cairncross, Stephen Yip, Emma Laks, Samuel AJR Aparicio, Jennifer A Chan, Chistopher S Hughes, Gregg B Morin, Veronique G LeBlanc, Marco A Marra bioRxiv 533323; doi: https://doi.org/10.1101/533323
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:92534
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:31 Jan 2019 23:08
Last Modified:31 Jan 2019 23:08

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