Mechanism of Poly-ADP-ribose function in the spindle

Harvard University (Medical School), Boston MA

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Abstract

DESCRIPTION (provided by applicant): Poly ADP ribose (PAR) is a highly branched, negatively charged nucleic acid polymer which mediates the response to DNA damage, regulates transcription, and is involved in apoptosis. This diversity of function stems from its two mechanisms of activity; poly-ADP-ribosylation of proteins leads to a rapid and dramatic change in overall protein charge resulting in altered protein-protein interactions, and PAR functions as a structural matrix onto which nuclear proteins are sequestered due to non-covalent charge interactions. The extent of poly ADP ribosylation and the total amount of PAR are regulated by the balance of PAR polymerase (PARP) activity, which catalyze the transfer of ADP ribose from NAD onto acceptor proteins, and poly-ADP ribose glycohydrolase (PARG) activity, which hydrolyses the PAR polymer and frees it from the acceptor protein. While PARPs are best known as nuclear proteins, three of five identified PARPs localize to the mitotic spindle suggesting PAR may be important for spindle function. Preliminary experiments demonstrate a requirement for PAR in spindle function. Here, I propose to examine the mechanism by which PAR acts in the mitotic spindle.