Portal de Periódicos da CAPES

The COP9 signalosome is vital for timely repair of DNA double-strand breaks

2015; Oxford University Press; Volume: 43; Issue: 9 Linguagem: Inglês

10.1093/nar/gkv270

1362-4962

Michal Meir, Yaron Galanty, Lior Kashani, Michael Blank, Rami Khosravi, María Jesús Fernández-Ávila, Andrés Cruz-García, Ayelet Star, Lea Shochot, Y. Thomas, Lisa Garrett, Daniel Chamovitz, David M. Bodine, Thimo Kurz, Pablo Huertas, Yael Ziv, Yosef Shiloh,

Microtubule and mitosis dynamics

The DNA damage response is vigorously activated by DNA double-strand breaks (DSBs). The chief mobilizer of the DSB response is the ATM protein kinase. We discovered that the COP9 signalosome (CSN) is a crucial player in the DSB response and an ATM target. CSN is a protein complex that regulates the activity of cullin ring ubiquitin ligase (CRL) complexes by removing the ubiquitin-like protein, NEDD8, from their cullin scaffold. We find that the CSN is physically recruited to DSB sites in a neddylation-dependent manner, and is required for timely repair of DSBs, affecting the balance between the two major DSB repair pathways—nonhomologous end-joining and homologous recombination repair (HRR). The CSN is essential for the processivity of deep end-resection—the initial step in HRR. Cullin 4a (CUL4A) is recruited to DSB sites in a CSN- and neddylation-dependent manner, suggesting that CSN partners with CRL4 in this pathway. Furthermore, we found that ATM-mediated phosphorylation of CSN subunit 3 on S410 is critical for proper DSB repair, and that loss of this phosphorylation site alone is sufficient to cause a DDR deficiency phenotype in the mouse. This novel branch of the DSB response thus significantly affects genome stability.