DNA damage responses caused by Zmpste24 deficiency and lamin A mutation in premature ageing

Hutchinson‐Gilford progeria syndrome (HGPS) and restrictive dermopathy (RD) are two severe premature ageing diseases, which are caused by defective biogenesis of lamin A from prelamin A. Lamin A is a structural protein of the nuclear lamina that underlies the inner nuclear membrane. Truncation in lamin A or lack of functional Zmpste24, a protease responsible for prelamin A processing, results in premature ageing in mice and human. The underlying molecular mechanism is not understood. Here we present direct evidence showing that genomic integrity was compromised and DNA damage checkpoints were activated in Zmpste24‐deficient fibroblasts and HeLa cells transfected with truncated lamin A. By using the method of immunofluorescence microscopy, we found that in these two cell lines, mutant lamin A or prelamin A formed nucleoplasmic aggregates, colocalized with γ‐H2AX, a marker of DNA double strand breaks. The nuclear distribution of proteins required for DNA repair and DNA damage checkpoints, such as ATR, ATM and RPA, was altered to a pattern similar to that in UV‐irradiated cells. The similar phenotypes observed between the two cell lines indicate that the truncated lamin A produces a strong dominant negative effect on the endogenous lamin A. Our results suggest that defect in maintenance of genomic integrity in Zmpste24‐deficient cells and cells expressing truncated lamin A is a potential important cause of premature ageing.