Inhibition of Aurora-B kinase activity by poly(ADP-ribosyl)ation in response to DNA damage
Inhibition of Aurora-B kinase activity by poly(ADP-ribosyl)ation in response to DNA damage
复制标题
DOI：
10.1073/pnas.0506252102
复制
发表时间：
2005-10-04
影响因子：
11.1
通讯作者：
Sassone-Corsi, P
中科院分区：
文献类型：
--
作者：
Monaco, L;Kolthur-Seetharam, U;Sassone-Corsi, P
细胞周期调控的Aurora-B激酶是一种染色体乘客蛋白，与基本的有丝分裂事件有关，包括染色体对齐和分离以及纺锤体检查点功能。Aurora-B使组蛋白H3的丝氨酸10磷酸化，这一功能与有丝分裂染色质浓缩有关。我们发现，DNA损伤激活多聚ADP-核糖聚合酶(PARP)1会导致H3磷酸化的快速阻断。PARP-1是一种依赖NAD(+)的酶，在DNA损伤检测、修复和维持基因组稳定性方面发挥着多功能作用。在这里，我们证明了Aurora-B在物理上和特异性地与PARP-1的BRCT(BRCA-1 C-末端)结构域相关联。Aurora-B在DNA损伤后高度聚合(ADP-核糖基)，这种修饰导致其激酶活性显著抑制。高度相似的Aurora-A激酶不受PARP-1的调节。我们认为，PARP-1对Aurora-B激酶活性的特异性抑制参与了对DNA损伤的生理反应。
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.