WRN at telomeres: implications for aging and cancer

Abstract

Werner Syndrome (WS) is a fascinating autosomal recessive disorder affecting ~10 per million individuals (Epstein et al., 1966). Patients appear normal until the second decade of life, when they develop pathologies that phenocopy many aspects of normal human aging, including alopecia, ischemic heart disease, osteoporosis, bilateral ocular cataracts, type II diabetes mellitus, and hypogonadism (Thannhauser, 1945). WS patients also experience an increased risk of rare non-epithelial cancers, especially mesenchymal neoplasms such as sarcomas (Goto et al., 1996). Death usually occurs in the fourth decade from cardiovascular compromise or cancer. Fibroblasts isolated from WS patients characteristically senesce prematurely in culture (Faragher et al., 1993) and display increased chromosomal aberrations (Salk et al., 1981;Melcher et al., 2000). Since WS is caused by mutation of a single gene, WRN, these observations suggest that the WRN gene product functions to maintain genome stability.Cloning of WRN ten years ago revealed that it encodes a protein containing a highly conserved 3Ј to 5Ј DNA helicase domain of the RecQ family (reviewed by Martin and Oshima, 2000). RecQ helicase family members are involved in diverse biochemical processes, including DNA recombination, replication and repair, and WRN has been implicated in all of these (reviewed by Hickson, 2003). WRN also possesses several other conserved domains, including a 3Ј to 5Ј exonuclease domain, a nuclear localization sequence, and a multifunctional DNA/protein-binding domain (DPBD) that interacts with both DNA and proteins (reviewed by Orren, 2006). Through these domains WRN interacts with many factors that participate in diverse aspects of DNA metabolism beyond the scope of this commentary. Here, we focus on recent progress that indicates WRN might have a role at telomeres. Discussion of other aspects of WRN biology can be found elsewhere (Hickson, 2003; Comai and Li, 2004;Bohr, 2005;Orren, 2006). Telomere structure and maintenanceTelomeres are nucleoprotein structures that cap the ends of eukaryotic chromosomes and play crucial roles in maintaining genomic stability by providing both end-protection and a mechanism for generating chromosomal ends (LeBel and Wellinger, 2006). In mammals, telomeres consist of TTAGGG repetitive sequences that terminate in a 3Ј single-stranded Grich overhang. Telomeres can fold into a structure termed the t-loop, in which the 3Ј single-stranded overhang invades a duplex region of the telomere to sequester the overhang, forming a single-stranded displacement (D) loop (Griffith et al., 1999;Murti and Prescott, 1999). This telomeric conformation probably protects natural DNA ends from being recognized as double-strand breaks (DSBs) that would otherwise activate DNA damage checkpoint responses or participate in aberrant recombination events (reviewed by d'Adda di Fagagna et al., 2004). However, an extended telomeric conformation must also exist to facilitate replication of telomeres during S phase. Telomeres are maintained by the e...

The discovery of a Werner helicase interacting protein (WHIP) association with the nuclear pore complex

“…WHIP has multiple binding partners [32][33][34][35][36][37][38] and WRN also binds replication protein A, PCNA, DNA topoisomerase I and DNA polymerase. [39][40][41][42] The amino acid sequence of WHIP is similar to that of the replication factor C (RFC) family of clamp loader proteins but also contains a Walker A & B motif for ATPase activity (Fig. 1A).…”

WRN promoter methylation possibly connects mucinous differentiation, microsatellite instability and CpG island methylator phenotype in colorectal cancer

“…WRN (the Werner syndrome gene) and its product (DNA helicase 1 ) have been shown to be important in maintenance of telomere structures, 2 and initiation of DNA damage response after telomere disruption. 3 Normal telomere function is an important cellular mechanism against aging and manifestations of Werner syndrome.…”

Accelerated ageing: from mechanism to therapy through animal models

“…A Wrn-knockout mouse model recapitulates the alterations observed in WS patients at the molecular and cellular levels but, strikingly, Wrn deficiency does not causes an accelerated ageing phenotype in mice (Lombard et al 2000). In contrast, progeroid symptoms closely recapitulating WS develop in double-mutant mice lacking both Wrn and telomerase activity, revealing the critical role of Wrn in telomere biology and its relevance for the progeroid phenotypes caused by WRN deficiency (Chang et al 2004;Multani and Chang 2007). These findings indicate that mice and humans may show different sensitivity to progeroidcausing alterations, and these differences have to be carefully taken in consideration to interpret results derived from the use of murine models.…”