Cactins constitute a family of eukaryotic proteins broadly conserved from yeast to human and required for fundamental processes such as cell proliferation, genome stability maintenance, organismal development and immune response. Cactin proteins have been found to associate with the spliceosome in several model organisms, nevertheless their molecular functions await elucidation. Here we show that depletion of human cactin leads to premature sister chromatid separation, genome instability and cell proliferation arrest. Moreover, cactin is essential for efficient splicing of thousands of pre-mRNAs, and incomplete splicing of the pre-mRNA of sororin (also known as CDCA5), a cohesin-associated factor, is largely responsible for the aberrant chromatid separation in cactin-depleted cells. Lastly, cactin physically and functionally interacts with the spliceosome-associated factors DHX8 and SRRM2. We propose that cellular complexes comprising cactin, DHX8 and SRRM2 sustain precise chromosome segregation, genome stability and cell proliferation by allowing faithful splicing of specific pre-mRNAs. Our data point to novel pathways of gene expression regulation dependent on cactin, and provide an explanation for the pleiotropic dysfunctions deriving from cactin inactivation in distant eukaryotes.
The authors declare no competing or financial interests.
I.M.Y.Z., L.E.L. and C.M.A. designed the experiments. I.M.Y.Z. and L.E.L. performed the experiments and analyzed the data. C.S. performed the analysis of next generation sequencing data. I.M.Y.Z. and C.M.A. wrote the manuscript.
This work was supported by the European Research Council (BFTERRA) and the Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (Swiss National Science Foundation) (31003A_160338).
RNA sequencing data have been deposited in NCBI's Gene Expression Omnibus and are accessible through GEO Series accession number GSE82070 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE82070).
Supplementary information available online at http://jcs.biologists.org/lookup/doi/10.1242/jcs.194068.supplemental
- Received June 17, 2016.
- Accepted December 26, 2016.
- © 2017. Published by The Company of Biologists Ltd