Cellular dynamics and modulation of WRN protein is DNA damage specific.

The human premature aging protein Werner (WRN), deficient in Werner syndrome (WS), is localized mainly to the nucleolus in many cell types. DNA damage or replication arrest causes WRN to redistribute from the nucleolus to the nucleoplasm into discrete foci. In this study, we have investigated DNA damage specific cellular redistribution of WRN. In response to agents causing DNA double strand breaks or DNA base damage, WRN is re-distributed from the nucleolus to the nucleoplasm in a reversible manner. However, after ultraviolet (UV) irradiation such redistribution of WRN is largely absent. We also show that WRN is associated with the insoluble protein fraction of cells after exposure to various kinds of DNA damage but not after UV irradiation. Further, we have studied the DNA damage specific post-translational modulation of WRN. Our results show that WRN is acetylated after mytomycin C or methyl methane-sulfonate treatment, but not after UV irradiation. Also, DNA damage specific phosphorylation of WRN is absent in UV irradiated cells. Inhibition of phosphorylation fails to restore WRN localization. Thus, our results suggest that the dynamics of WRN protein trafficking is DNA damage specific and is related to its post-translational modulation. The results also indicate a preferred role of WRN in recombination and base excision repair rather than nucleotide excision repair.