Chromatin modifier MTA1 regulates mitotic transition and tumorigenesis by orchestrating mitotic mRNA processing

Jian Liu, Chunxiao Li, Jinsong Wang, Dongkui Xu, Haijuan Wang, Ting Wang, Lina Li, Hui Li, Peng Nan, Jingyao Zhang, Yang Wang, Changzhi Huang, Dong Chen, Yi Zhang, Tao Wen (), Qimin Zhan (), Fei Ma () and Haili Qian ()
Additional contact information
Jian Liu: Chinese Academy of Medical Sciences and Peking Union Medical College
Chunxiao Li: Chinese Academy of Medical Sciences and Peking Union Medical College
Jinsong Wang: Chinese Academy of Medical Sciences and Peking Union Medical College
Dongkui Xu: Chinese Academy of Medical Sciences and Peking Union Medical College
Haijuan Wang: Chinese Academy of Medical Sciences and Peking Union Medical College
Ting Wang: Chinese Academy of Medical Sciences and Peking Union Medical College
Lina Li: Capital Medical University
Hui Li: Chinese Academy of Medical Sciences and Peking Union Medical College
Peng Nan: Chinese Academy of Medical Sciences and Peking Union Medical College
Jingyao Zhang: Chinese Academy of Medical Sciences and Peking Union Medical College
Yang Wang: Dalian Medical University
Changzhi Huang: Chinese Academy of Medical Sciences and Peking Union Medical College
Dong Chen: ABLife Inc
Yi Zhang: ABLife Inc
Tao Wen: Capital Medical University
Qimin Zhan: Chinese Academy of Medical Sciences and Peking Union Medical College
Fei Ma: Chinese Academy of Medical Sciences and Peking Union Medical College
Haili Qian: Chinese Academy of Medical Sciences and Peking Union Medical College

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: Abstract Dysregulated alternative splicing (AS) driving carcinogenetic mitosis remains poorly understood. Here, we demonstrate that cancer metastasis-associated antigen 1 (MTA1), a well-known oncogenic chromatin modifier, broadly interacts and co-expresses with RBPs across cancers, contributing to cancerous mitosis-related AS. Using developed fCLIP-seq technology, we show that MTA1 binds abundant transcripts, preferentially at splicing-responsible motifs, influencing the abundance and AS pattern of target transcripts. MTA1 regulates the mRNA level and guides the AS of a series of mitosis regulators. MTA1 deletion abrogated the dynamic AS switches of variants for ATRX and MYBL2 at mitotic stage, which are relevant to mitosis-related tumorigenesis. MTA1 dysfunction causes defective mitotic arrest, leads to aberrant chromosome segregation, and results in chromosomal instability (CIN), eventually contributing to tumorigenesis. Currently, little is known about the RNA splicing during mitosis; here, we uncover that MTA1 binds transcripts and orchestrates dynamic splicing of mitosis regulators in tumorigenesis.

Date: 2020
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DOI: 10.1038/s41467-020-18259-1

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