Research Paper Volume 15, Issue 24 pp 14591—14606
SRSF7 downregulation induces cellular senescence through generation of MDM2 variants
- 1 Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon 16499, Korea
- 2 Inflamm-aging Translational Research Center, Ajou University Medical Center, Suwon 16499, Korea
- 3 Department of Biomedical Sciences, Graduate School of Ajou University, Suwon 16499, Korea
Received: August 10, 2023 Accepted: December 1, 2023 Published: December 29, 2023
https://doi.org/10.18632/aging.205420How to Cite
Copyright: © 2023 Hong et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Alternative splicing (AS) enables a pre-mRNA to generate different functional protein variants. The change in AS has been reported as an emerging contributor to cellular senescence and aging. However, it remains to be elucidated which senescent AS variants are generated in and regulate senescence. Here, we observed commonly down-regulated SRSF7 in senescent cells, using publicly available RNA-seq datasets of several in vitro senescence models. We further confirmed SRSF7 deregulation from our previous microarray datasets of time-series replicative senescence (RS) and oxidative stress-induced senescence (OSIS) of human diploid fibroblast (HDF). We validated the time-course changes of SRSF mRNA and protein levels, developing both RS and OSIS. SRSF knockdown in HDF was enough to induce senescence, accompanied by p53 protein stabilization and MDM2 variants formation. Interestingly, expression of MDM2 variants showed similar patterns of p53 expression in both RS and OSIS. Next, we identified MDM2-C as a key functional AS variant generated specifically by SRSF7 depletion. Finally, we validated that MDM2-C overexpression induced senescence of HDF. These results indicate that SRSF7 down-regulation plays a key role in p53-mediated senescence by regulating AS of MDM2, a key negative regulator of p53, implying its critical involvement in the entry into cell senescence.
Abbreviations
AS: alternative splicing; DT: doubling time; GEO: Gene Expression Omnibus; GSEA: gene set enrichment analysis; HDF: human diploid fibroblast; hnRNP: heterogeneous nuclear ribonucleoprotein; MDM2-FL: MDM2 full-length; OSIS: oxidative stress-induced senescence; PD: population doubling; RBP: RNA binding protein; RS: replicative senescence; SA-β-gal: senescence-associated β-galactosidase; SF: splicing factor; SRSF: serine and arginine rich splicing factor.