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02 May 2003

Novel poly (ADP-ribose) polymerases: what do we know about their biological function?

G. de Murcia, J. Ame, C. Spenlehauer, V. Schreiber, F. Dantzer, A. Huber, C. Niedergang, L. Monaco, R. Loury, P. Sassone-Corsi, J. Menissier-de Murcia

Med Sci Monit 2003; 9(1): 48- :: ID: 15111

Abstract

During the past few years a large number of new poly (ADP-ribose) polymerases (PARPs) have been discovered using genetic screens and sequence database searches [1]. To date, a total of 18 distinct cDNA sequences encoding a corresponding number of PARP homologues have been identified. A multiple alignment of the PARP domain reveals major conservation blocks forming the ‘PARP signature’. The PARP superfamily can be divided into: (i) the PARP-1 group containing PARP-2, -3, -4 (VPARP) [2], -6 and -8 and (ii) the Tankyrases [3] with a sub-group containing PARP-7, -11, -12, -13, -14, -15 and –16. Interestingly, the subcellular distribution of the first five PARPs reveal their transient or permanent association with the mitotic apparatus, suggesting their involvement in the control of the mitotic fidelity.This presentation focuses on the importance of PARP activity in the maintenance of genomic stability during mitosis with a particular emphasis on PARP-1, -2 and -3. Novel connections between PARPs and key players of the metaphase/anaphase transition will be discussed. Notably, the cross-talk between PARP and Aurora B, a mitotic kinase that regulates chromosome condensation/segregation [4] and cytokinesis will be presented.Together with the recent results obtained with the Drosophila model [5], poly(ADP-ribosyl)ation reactions appear to contribute critically to the control of chromatin structure in facultative (X-chromosome) or constitutive (centromeres) heterochromatin and when chromatin loosening is required like in DNA repair or transcription in Drosophila puff loci. Therefore poly(ADP-ribosyl)ation should be recognized as an epigenetic mechanism that, per se, or in combination with other modifications contributes to the histone code. References: 1.de Murcia G, Shall S: From DNA damage and stress signaling to cell death. Poly ADP-ribosylation reactions. Oxford University Press, Oxford 2000, UK 2.Kickhoefer VA et al: J Cell Biol, 1999; 146: 917-928 3.Smith S et al: Science, 1998; 282: 1484-1487 4.Crosio C et al: Mol Cell Biol, 2002; 22: 874-885 5.Tulin A, Spradling A: Science, 2003; 299: 560-562

Keywords: NAD metabolism, genomic instability, histone code

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