Priority Research Paper Volume 13, Issue 10 pp 13380—13392
Cdkn1a transcript variant 2 is a marker of aging and cellular senescence
- 1 Buck Institute for Research on Aging, Novato, CA 94945, USA
- 2 Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Campus de Excelencia Internacional Agroalimentario, 14071, Córdoba, Spain
- 3 Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago 2422, Chile
- 4 Geroscience Center for Brain Health and Metabolism, Santiago, Chile
- 5 Unity Biotechnology Inc., South San Francisco, CA 94080, USA
- 6 Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA 93106, USA
- 7 Lawrence Berkeley National Laboratory, University of California, Berkeley, CA 94720, USA
Received: March 16, 2021 Accepted: May 18, 2021 Published: May 25, 2021https://doi.org/10.18632/aging.203110
How to Cite
Copyright: © 2021 López-Domínguez et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Cellular senescence is a cell fate response characterized by a permanent cell cycle arrest driven primarily the by cell cycle inhibitor and tumor suppressor proteins p16Ink4a and p21Cip1/Waf1. In mice, the p21Cip1/Waf1 encoding locus, Cdkn1a, is known to generate two transcripts that produce identical proteins, but one of these transcript variants is poorly characterized. We show that the Cdkn1a transcript variant 2, but not the better-studied variant 1, is selectively elevated during natural aging across multiple mouse tissues. Importantly, mouse cells induced to senescence in culture by genotoxic stress (ionizing radiation or doxorubicin) upregulated both transcripts, but with different temporal dynamics: variant 1 responded nearly immediately to genotoxic stress, whereas variant 2 increased much more slowly as cells acquired senescent characteristics. Upon treating mice systemically with doxorubicin, which induces widespread cellular senescence in vivo, variant 2 increased to a larger extent than variant 1. Variant 2 levels were also more sensitive to the senolytic drug ABT-263 in naturally aged mice. Thus, variant 2 is a novel and more sensitive marker than variant 1 or total p21Cip1/Waf1 protein for assessing the senescent cell burden and clearance in mice.