Reactome | ATR activation at DNA DSBs

ATR activation at DNA DSBs

Stable Identifier

R-HSA-5685011

Type

Reaction [binding]

Species

Homo sapiens

Compartment

nucleoplasm

ReviewStatus

5/5

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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
15189136	Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints Lindsey-Boltz, LA, Sancar, A, Unsal-Kaçmaz, K, Linn, S	Annu. Rev. Biochem.	2004
21263215	CtIP interacts with TopBP1 and Nbs1 in the response to double-stranded DNA breaks (DSBs) in Xenopus egg extracts Ramírez-Lugo, JS, Yoon, SJ, Dunphy, WG, Yoo, HY	Cell Cycle	2011
23345434	Nek1 kinase associates with ATR-ATRIP and primes ATR for efficient DNA damage signaling Zou, L, Liu, S, Ouyang, J, Ho, CK	Proc. Natl. Acad. Sci. U.S.A.	2013
21777809	ATR autophosphorylation as a molecular switch for checkpoint activation Yang, XH, Lahiri, M, Zou, L, Shiotani, B, Tse, A, Maréchal, A, Liu, S, Glover, JN, Leung, CC	Mol. Cell	2011
17575048	The Rad9-Hus1-Rad1 (9-1-1) clamp activates checkpoint signaling via TopBP1 Delacroix, S, Karnitz, LM, Wagner, JM, Yamamoto, K, Kobayashi, M	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 Lindsey-Boltz, LA, Hurwitz, J, Maniwa, Y, Sancar, A, Cesare, AJ, Bermudez, VP, Griffith, JD	Proc Natl Acad Sci U S A	2003
16530042	TopBP1 activates the ATR-ATRIP complex Dunphy, WG, Lee, J, Kumagai, A, Yoo, HY	Cell	2006
21659603	A DNA damage response screen identifies RHINO, a 9-1-1 and TopBP1 interacting protein required for ATR signaling Hurov, K, Elledge, SJ, Cotta-Ramusino, C, McDonald, ER, Sowa, ME, Harper, JW	Science	2011