PerspectiveStructural Biology

PARP-1 Activation—Bringing the Pieces Together

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Science  11 May 2012:
Vol. 336, Issue 6082, pp. 678-679
DOI: 10.1126/science.1221870

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The repair of DNA strand breaks is crucial for cell survival. In higher eukaryotes, cellular responses to DNA strand breaks are coordinated by a process called poly(ADP-ribosyl)ation (where ADP is adenosine diphosphate). This highly dynamic process begins with the hydrolysis of NAD+ (nicotinamide adenine dinucleotide) by poly(ADP-ribose) polymerases (PARPs), resulting in the polymerization of ADP-ribose moieties onto a substrate protein. The most active PARP in DNA damage recognition, PARP-1, is highly stimulated by single- and double-strand breaks (1). Because it is a clinically important molecular target in the treatment of several cancers, including breast and ovarian cancers (2), understanding how PARP-1 is activated after binding DNA strand breaks is an ongoing challenge. On page 728 of this issue, Langelier et al. (3) report key structural information about PARP-1 domain organization around a DNA double-strand break (DSB) that explains this activation.