ATR activation at DNA DSBs

Stable Identifier
Homo sapiens
Locations in the PathwayBrowser

ATR:ATRIP complex is recruited to resected DNA double strand breaks (DSBs) via interaction with the RPA complex that coats single strand DNA (ssDNA) 3'-overhangs, but this is not sufficient for ATR to become catalytically active. ATR kinase activity requires the presence of the RAD17:RFC complex, RAD9:HUS1:RAD1 (9-1-1) complex and TOPBP1. RAD17:RFC loads RAD9:HUS1:RAD1 onto junctions of single strand and double strand DNA (ssDNA-dsDNA junctions), present at resected DNA DSBs (Bermudez et al. 2003, reviewed by Sancar et al. 2004). TOPBP1 binds the C-terminal tail of RAD9, and is thus brought in the proximity of ATR, where it can activate it (Kumagai et al. 2006, Delacroix et al. 2007). The interaction of TOPBP1 and RBBP8 (CtIP) also contributes to TOPBP1 loading (Ramirez-Lugo et al. 2011). Phosphorylation of ATR at threonine residue T1989 may create a binding site for the BRCT domains of TOPBP1 (Liu et al. 2011). It is not clear whether T1989 of ATR is phosphorylated through autophosphorylation (Liu et al. 2011), as it does not conform to the SQ/TQ consensus, or by another kinase (Liu et al. 2013). RHNO1 (RHINO) protein simultaneously binds RAD9:HUS1:RAD1 complex and TOPBP1 and is required for the full catalytic activation of ATR (Cotta-Ramusino et al. 2011).

Participant Of
Orthologous Events