Role of poly(ADP-ribose) formation in DNA repair

THE abundant nuclear enzyme poly(ADP-ribose) polymerase catalyses the synthesis of poly(ADP-ribose) from nicotinamide adenine dinucleotide (NAD+)1–5. This protein has an N-terminal DNA-binding domain containing two zinc-fingers, which is linked to the C-terminal NAD+-binding domain by a short region containing several glutamic acid residues that are sites of auto-poly(ADP-ribosyl)ation6–8. The intracellular production of poly(ADP-ribose) is induced by agents that generate strand interruptions in DNA7. The branched homopolymer chains may attain a size of 200–300 residues9 but are rapidly degraded after synthesis. The function of poly(ADP-ribose) synthesis is not clear, although it seems to be required for DNA repair10,11. Here we describe a human cell-free system that enables the role of poly(ADP-ribose) synthesis in DNA repair to be characterized. The results indicate that unmodified polymerase molecules bind tightly to DNA strand breaks; auto-poly(ADP-ribosyl)ation of the protein then effects its release and allows access to lesions for DNA repair enzymes.

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