WRN was orignially identified as a gene responsible for Werner Syndrome (WS; "Progeria of Adults"). The WRN gene consists of 35 exons that encode a protein of 1,432 amino acids (Yu et al., 1998). Sequence analysis suggested that the WRN protein may display exonuclease activity and act as a transcriptional activation factor.
There are two consensus domains in the C terminal region whose functions have not been completely elucidated (Morozov et al., 1997). However, biochemical studies suggest that the C terminal region contains both exonuclease activity (Huang et al., 1998) and helicase activity (Gray et al., 1997; Suzuki et al., 1997). This region was also shown to contain transactivation activity, which has been localized between the regions containing exonuclease and helicase activities (Ye et al., 1997; Barjee et al., 1998). Furthermore, the C-terminus is believed to contain the nuclear localization signal and may serve as a binding site for interacting proteins (Matsumoto et. al. 1997; Matsumoto et. al. 1998).
Indeed, the WRN protein is capable of a multitude of functions. These biochemical studies, combined with cell biological studies, suggested that this protein is potentially involved in DNA replication, repair, recombination, transcription and/or a combination of these events (e.g., repair during replication). However, the precise molecular mechanisms by which mutations in WRN cause the WS phenotype remain unknow. Recent progress in the understanding of the WRN protein and its implication in the normal aging process are discussed.
