Figure 8

Model summarizing results of this study. (1) Under non-stress conditions considerable fractions of cellular WRN, XRCC1, and PARP1 localize to nucleoli. (2) Upon genotoxic stress, in particular H₂O₂ treatment, all three proteins translocate from nucleoli to the nucleoplasm. (3) The translocation of WRN is fully dependent on PARP1 protein, but not on its enzymatic activity. (4) It is conceivable that upon nucleolar release, WRN binds by itself to specific types of DNA lesions or DNA repair intermediates and is thereby retained in the nucleoplasm until its tasks in DNA metabolism are fulfilled. (5) In contrast, a transient XRCC1 translocation can also occur in the absence of PARP1, potentially mediated by an unknown factor ‘Y’. Since XRCC1 by itself exhibits a BRCT domain, which may serve as a binding site to gossypol, it is conceivable that XRCC1 release from nucleoli is also inhibited by this substance. (6) XRCC1 requires DNA damage-bound and PARylated PARP1 as a loading platform, which leads to XRCC1 retention in the nucleoplasm until its tasks in BER are completed. (7) The latter hypothesis is supported by results revealing that in cells without PARP1 activity, XRCC1 relocates quickly to nucleoli.