Reactome | MRN activates ATM

MRN activates ATM

Stable Identifier

R-HSA-5693540

Type

Reaction [transition]

Species

Homo sapiens

Compartment

nucleoplasm

ReviewStatus

5/5

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MRN promotes dissociation of ATM dimers to ATM monomers which is accompanied by ATM trans-autophosphorylation on serine residue S1981 (Bakkenist et al. 2003, Du et al. 2014). ATM autophosphorylation at serine residues S367 and S1893 is also implicated in ATM activation (Kozlov et al. 2006). Dissociation of ATM dimers requires the ATP-dependent DNA-helicase activity of the MRN subunit RAD50 (Lee and Paull 2005). KAT5 (Tip60) mediated acetylation of ATM dimers at lysine K3016 is a prerequisite for ATM kinase activity (Sun et al. 2007). Upon the dissociation of ATM dimers induced by DNA double-strand breaks (DSBs), a fraction of activated ATM is retained at DSB sites, co-localizing with the MRN complex (Andegeko et al. 2001, Uziel et al. 2003) at ionizing radiation-induced foci (IRIF). MRN facilitates the binding of a portion of ATM substrates to ATM (Lee and Paull 2004).

After DSBs are repaired, ATM is dephosphorylated by an unidentified PP2A phosphatase complex, leading to dimer reformation (Goodarzi et al. 2004).

Literature References

PubMed ID	Title	Journal	Year
25240135	Dimer monomer transition and dimer re-formation play important role for ATM cellular function during DNA repair Meng, H, Xu, Y, Zhang, M, Du, F, Chang, S, Sun, Y, Yang, C, Price, B, Li, X, Wang, D	Biochem. Biophys. Res. Commun.	2014
15064416	Direct activation of the ATM protein kinase by the Mre11/Rad50/Nbs1 complex Lee, JH, Paull, TT	Science	2004
12556884	DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation Kastan, MB, Bakkenist, CJ	Nature	2003
17923702	DNA damage-induced acetylation of lysine 3016 of ATM activates ATM kinase activity Xu, Y, Sun, Y, Roy, K, Price, BD	Mol. Cell. Biol.	2007
15510216	Autophosphorylation of ataxia-telangiectasia mutated is regulated by protein phosphatase 2A Ye, R, Douglas, P, Jonnalagadda, JC, Lees-Miller, SP, Goodarzi, AA, Young, D, Khanna, KK, Moorhead, GB	EMBO J.	2004
16858402	Involvement of novel autophosphorylation sites in ATM activation Graham, ME, Kozlov, SV, Chen, P, Lavin, MF, Peng, C, Robinson, PJ	EMBO J.	2006
14532133	Requirement of the MRN complex for ATM activation by DNA damage. Shiloh, Y, Mittelman, L, Lerenthal, Y, Andegeko, Y, Uziel, T, Moyal, L	EMBO J	2003
11454856	Nuclear retention of ATM at sites of DNA double strand breaks Moyal, L, Andegeko, Y, Mittelman, L, Rotman, G, Tsarfaty, I, Shiloh, Y	J. Biol. Chem.	2001
15790808	ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex Paull, TT, Lee, JH	Science	2005