Patients with Hutchinson-Gilford progeria syndrome (HGPS) and restrictive dermopathy (RD) age extremely quickly. In both diseases, processing of farnesylated prelamin A into lamin A (a component of the nuclear lamina that supports the nucleus and organizes chromatin) is defective, but why this accelerates aging is unclear. Now, Yue Zou and colleagues report that DNA damage checkpoints are constantly activated in HGPS and RD cells (as they are in normally aged cells) because of DNA damage caused by accumulated prelamin A (see p. 4644). The authors show that the checkpoint kinases ATM (ataxia-telangiectasia-mutated) and ATR (ATM- and Rad3-related) and their downstream effectors are activated in HGPS and RD fibroblasts. Inactivation of ATM and ATR partly overcomes the resultant replication arrest, but treatment with a farnesyltransferase inhibitor (which corrects the aberrant nuclear morphology of these cells) does not reduce DNA damage or checkpoint signalling. Thus, suggest the authors, prelamin A accumulation causes DNA damage and abnormal nuclear morphology by distinct mechanisms, and treatments for HGPS and RD will need to target both phenotypes.
Checkpoints signal premature ageing
Checkpoints signal premature ageing. J Cell Sci 15 November 2006; 119 (22): e2202. doi:
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