Inhibition of Aurora-B kinase activity by poly(ADP-ribosyl)ation in response to DNA damage

L. Monaco , U. Kolthur-Seetharam , R. Loury , J. M. Murcia , G. de Murcia (1) , P. Sassone-Corsi

1 Institut Gilbert-Laustriat : Biomolécules, Biotechnologie, Innovation Thérapeutique

The cell cycle-regulated Aurora-B kinase is a chromosomal passenger protein that is implicated in fundamental mitotic events, including chromosome alignment and segregation and spindle checkpoint function. Aurora-B phosphorylates serine 10 of histone H3, a function that has been associated with mitotic chromatin condensation. We find that activation of poly(ADP-ribose) polymerase (PARP) 1 by DNA damage results in a rapid block of H3 phosphorylation. PARP-1 is a NAD(+)-dependent enzyme that plays a multifunctional role in DNA damage detection and repair and maintenance of genomic stability. Here, we show that Aurora-B physically and specifically associates with the BRCT (BRCA-1 C-terminal) domain of PARP-1. Aurora-B becomes highly poly(ADP-ribosyl)ated in response to DNA damage, a modification that leads to a striking inhibition of its kinase activity. The highly similar Aurora-A kinase is not regulated by PARP-1. We propose that the specific inhibition of Aurora-B kinase activity by PARP-1 contributes to the physiological response to DNA damage.

Mots clés: Animals; Blotting; Western; COS Cells; Cercopithecus aethiops; Comparative Study; DNA Damage; Histones/metabolism; Immunoprecipitation; Mice; NIH 3T3 Cells; Phosphorylation; Poly Adenosine Diphosphate Ribose/*metabolism; Poly(ADP-ribose) Polymerases/*metabolism; Protein-Serine-Threonine Kinases/*metabolism; Proteins/*metabolism; Research Support; Non-U.S. Gov't

L. Monaco, U. Kolthur-Seetharam, R. Loury, J. M. Murcia, G. de Murcia, et al.. Inhibition of Aurora-B kinase activity by poly(ADP-ribosyl)ation in response to DNA damage. Proceedings of the National Academy of Sciences of the United States of America, 2005, 102, pp.14244-8. ⟨hal-00129937⟩