Molecular Cell, Volume 33, Issue 5, 547-558, 13 March 2009
Article
Single-Stranded DNA Orchestrates an ATM-to-ATR Switch at DNA Breaks
Bunsyo Shiotani1andLee Zou1,2,Go To Corresponding Author,
1 Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA 2 Department of Pathology, Harvard Medical School, Boston, MA 02115, USA


Summary

ATM and ATR are two master checkpoint kinases activated by double-stranded DNA breaks (DSBs). ATM is critical for the initial response and the subsequent ATR activation. Here we show that ATR activation is coupled with loss of ATM activation, an unexpected ATM-to-ATR switch during the biphasic DSB response. ATM is activated by DSBs with blunt ends or short single-stranded overhangs (SSOs). Surprisingly, the activation of ATM in the presence of SSOs, like that of ATR, relies on single- and double-stranded DNA junctions. In a length-dependent manner, SSOs attenuate ATM activation and potentiate ATR activation through a swap of DNA-damage sensors. Progressive resection of DSBs directly promotes the ATM-to-ATR switch invitro. In cells, the ATM-to-ATR switch is driven by both ATM and the nucleases participating in DSB resection. Thus, single-stranded DNA orchestrates ATM and ATR to function in an orderly and reciprocal manner in two distinct phases of DSB response.