Alternative splicing regulation of cell-cycle genes by SPF45/SR140/CHERP complex controls cell proliferation

  1. Juan Valcárcel1,2,3
  1. 1Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona 08003, Spain
  2. 2Universitat Pompeu Fabra (UPF), Barcelona 08003, Spain
  3. 3Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain
  1. Corresponding author: juan.valcarcel{at}crg.eu
  • 4 Present address: The Francis Crick Institute, London NW1 1AT, UK

Abstract

The regulation of pre-mRNA processing has important consequences for cell division and the control of cancer cell proliferation, but the underlying molecular mechanisms remain poorly understood. We report that three splicing factors, SPF45, SR140, and CHERP, form a tight physical and functionally coherent complex that regulates a variety of alternative splicing events, frequently by repressing short exons flanked by suboptimal 3′ splice sites. These comprise alternative exons embedded in genes with important functions in cell-cycle progression, including the G2/M key regulator FOXM1 and the spindle regulator SPDL1. Knockdown of either of the three factors leads to G2/M arrest and to enhanced apoptosis in HeLa cells. Promoting the changes in FOXM1 or SPDL1 splicing induced by SPF45/SR140/CHERP knockdown partially recapitulates the effects on cell growth, arguing that the complex orchestrates a program of alternative splicing necessary for efficient cell proliferation.

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Footnotes

  • Received August 2, 2021.
  • Accepted September 11, 2021.

This article, published in RNA, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.

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