1. Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, and
2. Departamento de Morfología y Biología Celular, Universidad de Oviedo, 33006 Oviedo, Spain
3. Division of Matrix Biology, Department of Biochemistry and Biophysics, Karolinska Institutet, Stockholm S-17177, Sweden
4. National Cancer Institute, Frederick, Maryland 21702, USA
5. *These authors contributed equally to this work
6. †Present address: Department of Biochemistry, Facult of Medicine, University of Hong Kong, Pok Fu Lam, Hong Kong

Correspondence to: Carlos López-Otín¹ Correspondence and requests for materials should be addressed to C.L.-O. (Email: clo@uniovi.es).

Abstract

Zmpste24 (also called FACE-1) is a metalloproteinase involved in the maturation of lamin A (Lmna), an essential component of the nuclear envelope^{1, 2, 3}. Both Zmpste24- and Lmna-deficient mice exhibit profound nuclear architecture abnormalities and multiple histopathological defects that phenocopy an accelerated ageing process^{1, 2, 4, 5}. Similarly, diverse human progeroid syndromes are caused by mutations in ZMPSTE24 or LMNA genes^{6, 7, 8, 9, 10}. To elucidate the molecular mechanisms underlying these devastating diseases, we have analysed the transcriptional alterations occurring in tissues from Zmpste24-deficient mice. We demonstrate that Zmpste24 deficiency elicits a stress signalling pathway that is evidenced by a marked upregulation of p53 target genes, and accompanied by a senescence phenotype at the cellular level and accelerated ageing at the organismal level. These phenotypes are largely rescued in Zmpste24^-/-Lmna^+/- mice and partially reversed in Zmpste24^-/-p53^-/- mice. These findings provide evidence for the existence of a checkpoint response activated by the nuclear abnormalities caused by prelamin A accumulation, and support the concept that hyperactivation of the tumour suppressor p53 may cause accelerated ageing¹¹.

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