Cellular Function, Including Centrosome Duplication, by Poly ADP-Ribosyl ation

Control of Cellular Function, Including Centrosome Duplication, by Poly(ADP-Ribosyl)ation 

Previous studies had shown that PARP-1 is mainly localized to the nucleus. However from the pattern of chromosome instability in PARP-1 knockout mouse cells, we speculated that PARP-1 might also be localized to another component related to the mitotic machinery. Indeed, we found PARP-1 localized to the centrosome in some cancer cells and mouse embryonic fibroblasts (MEF). The localization of PARP-1 at the centrosome su ested the possibility that PARP-1 at the centrosome could catalyze poly(ADP-ribosyl)ation of certain centrosomal proteins. In fact we could observe the presence of various bands in western blots of the centrosomal proteins that reacted with a monoclonal antibody to polyfADP-ribose) (lOH). These results showed the involvement of PARP-1-mediated poly(ADP-ribosyl)ation in centrosome regulation. 

It is important to identify each of the poly(ADP-ribosyI)ated proteins in order to clarify the role of poly(ADP-ribosyl)ation. Indeed we have identified some proteins that are poly(ADP-ribosyl)ated in the centrosome. One of these proteins is the tumor suppressor protein p33. p33 is a well known guardian of the genome, and it is essential for DNA repair and apoptosis. Interestingly, p33 also localizes to the centrosome and r ubites centrosome fonaion directly or indirectly. Our study revealed that inhibition of poly(ADP-ribosyl)arion of p33 due to administration of a PARP inhibitor or loss of PARP-1 mi t be involved in the defect in centrosome function and chromosomal instability. 

Out data show that there are many proteins that arc poly(ADP-ribosyl)ated. In view of the dynamic process of poly(ADP-ribosyl)ation, a posttranslational modification undergoing rapid turnover, the recent discovery that poly(ADP-ribose) glycohydrolase (PARC) is also localized in the centrosome durii the cell cycle is very interesting and plausible. 

Identification of the poly(ADP-ribosyl)ated centrosomal proteins and clarification of the changes in subcellular localization by possible shutding between the centrosome and the nucleus will be essential for further understanding the role of poly(ADP-ribosyl)ation. It would also be very interesting to know the trigger(s) of poly(ADP-ribosyl)ation in the centrosome, since it is believed that this structure is devoid of DNA. Such analyses would clarify a novel mechanism of the regulation of the centrosome function by posttranslational poly(ADP-ribosyl)ation. 

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