Diverged nuclear localization of Werner helicase in human and mouse cells

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Abstract
Werner syndrome (WS) is a rare autosomal recessive genetic disorder causing premature aging and rare cancers. A gene responsible for WS (WRN) encodes a protein with 1432 amino acids (a.a.) homologous to the E. coli RecQ-type DNA helicase. Transcriptional activation facilitated nucleolar localization of human WRN protein (hWRNp) and serum starvation induced translocation of hWRNp from the nucleoli to the nucleoplasm in human cultured cells, suggesting a nucleolar-nucleoplasm trafficking of hWRNp depending on transcriptional state. Mutant hWRNp lacking the C-terminal 30 a.a. residues (Delta1403-1432) failed to localize in the nucleolus, whereas Delta1405-1432 can migrate into the nucleolus. Here we identify a region putative for nucleolar localization signal (NoLS) containing a sequence of two positively charged amino acids (Arg(1403)-Lys(1404)) in the C-terminal area of hWRNp. By contrast, the mouse homolog (mWRNp) exists only in the nucleoplasm. We show that the inability of mWRNp to migrate into the nucleolus is due to a difference of a sequence in the region corresponding to the NoLS of hWRNp. In addition, mouse cells cannot recognize the NoLS of hWRNp. Our study suggests that defect in nucleolar function of hWRNp may be linked to the premature aging which is not observed in mWRN(-/-) mice.