Nuclear matrix-associated poly(adpribosyl)ation system in rat hepatocytes during the acute phase reaction

Abstract

Poly (ADPribosyl) polymerase (PARP) is a 113 kD nuclear protein. Following activation by DNA strand breaks, PARP hydrolyzes NAD+ and catalyzes the formation of poly(ADP-ribose) onto itself (automodification) and other nuclear proteins (heteromodification) with the release of nicotinamide. Poly(ADPribosyl)ation is an event of major importance. It participates in fundamental processes such as DNA repair, replication, cell cycle regulation and apoptosis (d 'A m 0 u r s etai.1999). PARP also participates in the regulation of transcription. It appears to exert a dual function in this process: stimulation and inhibition. In the absence of catalytic activity, PARP has been shown to be a component of the pre-initiation transcription complex. On the other hand, protein modification with poly (ADPribose) is an efficient means of reversibly silencing polymerase Il-dependent transcription (0 e i et al. 1998a). Consequently, the activating or repressing influence of PARP on transcription depends on its catalytic activity. Poly (ADPribosyl)ation occurs only if it is initiated before the acceptor protein binds to DNA and thereby prevents the formation of active transcription complexes. Otherwise, the binding of the acceptor protein to DNA prevents its modification. Recently, it was shown that the catalytically active PARP moiety can cause silencing of transcription. It modifies transcription factorsY'Yl (0 e i et al. 2001b), p53 (We s i e r s k a Gad e k et ai. 19(6), TBP (0 e i et ai. 1998c) and FOS (A m s tad et al. 1992) by poly (ADPribosyl) ation, thereby interfering with their DNA-binding affinity. PARP exists in a form that is associated with the nuclear matrix (d' E r m e 1990). The nuclear matrix, the main structural framework of the nucleus, is a nonhistone protein scaffold that supports the attachment points of DNA loops (B ere z n e y and Wei 1998; La e m m I i et ai. 1992). It is now widely accepted that fundamental processes of the cell nucleus are actively coordinated by the nuclear matrix. DNA replication, transcription, mRNA processing and DNA repair occur on the nuclear matrix (T u b 0 and B ere z n e y 1987). Some of the protein components of the nuclear matrix appear to be poly(ADPribosyl)ated (B err i 0 s et ai. 1985), whereas others are tightly associated with PARP, suggesting a modulatory role of the nuclear matrix-associated PARP in nuclear functions. In light of the potential role of PARP in certain nuclear matrix-mediated functions, we examined the role of the nuclear matrix-associated poly (ADPribosyl) ation system in transcriptional regulation. The experimental model system of