MRN activates ATM

Stable Identifier
R-HSA-5693540
Type
Reaction
Species
Homo sapiens
Compartment
Locations in the PathwayBrowser
Summation

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 the DNA double strand breaks (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
15064416 Direct activation of the ATM protein kinase by the Mre11/Rad50/Nbs1 complex

Lee, JH, Paull, TT

Science 2004
25240135 Dimer monomer transition and dimer re-formation play important role for ATM cellular function during DNA repair

Du, F, Zhang, M, Li, X, Yang, C, Meng, H, Wang, D, Chang, S, Xu, Y, Price, B, Sun, Y

Biochem. Biophys. Res. Commun. 2014
12556884 DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation

Bakkenist, CJ, Kastan, MB

Nature 2003
17923702 DNA damage-induced acetylation of lysine 3016 of ATM activates ATM kinase activity

Sun, Y, Xu, Y, Roy, K, Price, BD

Mol. Cell. Biol. 2007
15510216 Autophosphorylation of ataxia-telangiectasia mutated is regulated by protein phosphatase 2A

Goodarzi, AA, Jonnalagadda, JC, Douglas, P, Young, D, Ye, R, Moorhead, GB, Lees-Miller, SP, Khanna, KK

EMBO J. 2004
16858402 Involvement of novel autophosphorylation sites in ATM activation

Kozlov, SV, Graham, ME, Peng, C, Chen, P, Robinson, PJ, Lavin, MF

EMBO J. 2006
14532133 Requirement of the MRN complex for ATM activation by DNA damage.

Uziel, T, Lerenthal, Y, Moyal, L, Andegeko, Y, Mittelman, L, Shiloh, Y

EMBO J 2003
11454856 Nuclear retention of ATM at sites of DNA double strand breaks

Andegeko, Y, Moyal, L, Mittelman, L, Tsarfaty, I, Shiloh, Y, Rotman, G

J. Biol. Chem. 2001
15790808 ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex

Lee, JH, Paull, TT

Science 2005
Participants
Participant Of
Catalyst Activity
Catalyst Activity
Title
protein serine/threonine kinase activity of DNA DSBs:MRN:Ac-K3016-ATM dimer:KAT5 [nucleoplasm]
Physical Entity
Activity
Orthologous Events
Authored
Reviewed