ATR activation at DNA DSBs

Stable Identifier
Homo sapiens
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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).

Literature References
PubMed ID Title Journal Year
21263215 CtIP interacts with TopBP1 and Nbs1 in the response to double-stranded DNA breaks (DSBs) in Xenopus egg extracts

Ramírez-Lugo, JS, Yoo, HY, Yoon, SJ, Dunphy, WG

Cell Cycle 2011
15189136 Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints

Sancar, A, Lindsey-Boltz, LA, Unsal-Kaçmaz, K, Linn, S

Annu. Rev. Biochem. 2004
23345434 Nek1 kinase associates with ATR-ATRIP and primes ATR for efficient DNA damage signaling

Liu, S, Ho, CK, Ouyang, J, Zou, L

Proc. Natl. Acad. Sci. U.S.A. 2013
21777809 ATR autophosphorylation as a molecular switch for checkpoint activation

Liu, S, Shiotani, B, Lahiri, M, Maréchal, A, Tse, A, Leung, CC, Glover, JN, Yang, XH, Zou, L

Mol. Cell 2011
17575048 The Rad9-Hus1-Rad1 (9-1-1) clamp activates checkpoint signaling via TopBP1

Delacroix, S, Wagner, JM, Kobayashi, M, Yamamoto, K, Karnitz, LM

Genes Dev 2007
12578958 Loading of the human 9-1-1 checkpoint complex onto DNA by the checkpoint clamp loader hRad17-replication factor C complex in vitro

Bermudez, VP, Lindsey-Boltz, LA, Cesare, AJ, Maniwa, Y, Griffith, JD, Hurwitz, J, Sancar, A

Proc Natl Acad Sci U S A 2003
16530042 TopBP1 activates the ATR-ATRIP complex

Kumagai, A, Lee, J, Yoo, HY, Dunphy, WG

Cell 2006
21659603 A DNA damage response screen identifies RHINO, a 9-1-1 and TopBP1 interacting protein required for ATR signaling

Cotta-Ramusino, C, McDonald, ER, Hurov, K, Sowa, ME, Harper, JW, Elledge, SJ

Science 2011
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