Ding and Shen individual telomeres (Crabbe et al 2004). Accelerated loss of telomere reserves and activation of cellular checkpoints appear integral to the decreased replicative potential seen in WS, as evidenced by the capacity of enforced TERT expression to impart unlimited replicative potential (Wyllie et al 2000). WRN functionally interacts with a number of proteins involved in telomere length maintenance, including Ku 70/86 (Orren et al 2001), RPA (Brosh et al 1999, 2000; Sanz et al 2000), TRF1, and TRF2 (Opresko et al 2002, 2004; Machwe et al 2004). RPA is a single strand DNA-binding protein that is required for all aspects of DNA metabolism (Brosh et al 2000), while TRF1 and TRF2 are homodimeric proteins that have been shown to bind exclusively to double stranded telomeric DNA throughout the cell cycle and are thought to be involved in the regulation of telomeric length (Fairall et al 2001). TRF2 as a promoter for the helicase activity of WRN, the interaction between WRN and TRF2 may serve to stabilize TRF2 in its active form or to improve TRF2’s interaction with DNA (Opresko et al 2002). Due to the absence of WRN in WS patients, TRF2 is unable to perform its duty and telomeric-speciﬁc structures that need to be degraded are not (Grifﬁth 1999; Opresko 2002; Jeziorny 2006). These structures then act as barriers against various transcription factors and telomeres are left without being fully transcribed. Taken together, these results suggest that WRN is necessary for the efﬁcient replication of G-rich telomeric DNA and that WRN deﬁciency and dysfunctional telomeres appear to act cooperatively to increase the overall level of genomic instability, triggering the onset of premature aging phenotypes (Orren et al 2001; Opresko et al 2002, 2004). DNA apoptosis A link between WRN and apoptosis was ﬁrst proposed by studies demonstrating that WS ﬁbroblasts exhibit a decreased p53- mediated apoptotic response, and this deﬁciency can be rescued by expression of wild-type WRN (Spillare et al 1999). p53 is a key cellular component in maintaining genomic stability either by regulating the cell cycle to allow DNA repair or by inducing apoptosis (Haupt et al 2003; Hofseth et al 2004; Lane 2004). The C-terminus of WRN binds to the C-terminal domain of p53 to induce p53-mediated apoptosis (Clarke et al 1993; Symonds et al 1994; Wang et al 1996, 2001; Spillare et al 1999; Brosh et al 2001a). Fibroblasts from WS patients have a decreased ability to undergo p53-mediated apoptosis (Spillare et al 1999), so 436 the absence of WRN-p53 direct interaction could serve as a signal for programmed cell death. Moreover, the expression of wild-type WRN is sufﬁcient to rescue WS¯/¯ cells from the attenuation of p53-mediated apoptosis (Spillare et al 1999; Blander et al 2001). p53 may exert its effect on WRN by its interaction with RPA. Overexpression of p53 results in a decrease in Sp-1-mediated transcription of the WRN gene, suggesting that p53 regulates WRN expression (Yamabe et al 1998). Thus, the interaction of WRN with p53 and/or the WRN-RPA complex may be critical in preventing entry into S phase or in directing S phase cells towards apoptosis. The absence of a p53-WRN helicase interaction may disrupt the signal to direct S-phase cells into apoptosis for programmed cell death and contribute to the pronounced genomic insta- bility and cancer predisposition seen in WS cells (Sommers et al 2005). In addition, epigenetic inactivation (promoter hypermethylation) of WRN can lead to the loss of WRN- associated exonuclease activity and increased chromosomal instability and apoptosis induced by topoisomerase inhibitors (Agrelo et al 2006). Hutchinson-Gilford progeria syndrome Hutchinson-Gilford progeria syndrome, a childhood progeroid disorder, is a rare, fatal genetic disorder charac- terized by segmental accelerated aging. Affected children appear normal at birth, but within a year develop character- istic features of failure to thrive, delayed dentition, alopecia, atherosclerosis, prominent scalp veins, a high pitched voice, and sclerodermatous skin changes, with death at approxi- mately 13 years from atherosclerosis of the coronary and cerebrovascular arteries. Eriksson and colleagues (2003) identiﬁed the disease causing mutations in the LMNA gene (encoding lamin A/C). The vast majority of HGPS cases are caused by a single-base substitution (GGC GGT), which does not cause an amino acid change (G608G), but results in deletion of 150 nucleotides in exon 11, causing an alternatively spliced truncated variant of lamin A mRNA and an in-frame deletion of 50 amino acids near the carboxy terminus, leading to changes in the nuclear architecture (De Sandre-Giovannoli et al 2003; Eriksson et al 2003). Other HGPS mutations that have been described in LMNA include E145K, R471C, R527C, G608S, T623S, and 1824C T (Cao and Hegele 2003; Csoka et al 2004a; Fukuchi et al 2004). Lamins form microﬁlaments in the nucleus and are important in maintaining the proper structure of the nuclei, but they also inﬂuence on chromatin structure, regula- tion of gene expression, localization and probably protein Clinical Interventions in Aging 2008:3(3)