Cryo-EM structure of the Mre11-Rad50-Nbs1 complex reveals the molecular mechanism of scaffolding functions

Importance of Germline and Somatic Alterations in Human MRE11, RAD50, and NBN Genes Coding for MRN Complex

“…The MRN complex consists of a symmetrical dimer assembled from two MRE11, RAD50 protomers (M 2 R 2 ) that are stabilized by NBN protein(s) [ 13 ]. The entire complex is a dynamic molecular structure consisting of a globular DNA binding domain and two coiled-coil arms protruding 60 nm apart [ 14 ]. Although the detailed molecular structure of the human MRN complex has not yet been solved, its structure should be similar in other species ( Figure 1 ) due to the high conservation of structural and functional features of the MRN complex [ 15 , 16 , 17 , 18 ].…”

“…Recent cryoelectron microscopy analysis of the eukaryotic MRN complex from Ch. thermophilum by Rotheneder and colleagues described a global architecture, revealing a rod-like assembly of RAD50 dimers protruding with their CC domains 60 nm apart from a complex of RAD50 globular head with MRE11 homodimer stabilized by an asymmetrically-bound single NBN molecule [ 14 ]. Despite that this work shed light on the possible composition of the human MRN complex, many important questions remained unanswered, including its dynamics during the DSB repair or the composition of the NBN subunit and its interaction with binding partners, including ATM or CtIP [ 48 ].…”

Binding of the TRF2 iDDR motif to RAD50 highlights a convergent evolutionary strategy to inactivate MRN at telomeres

“…binding and tethering, as well as for Tel1/ATM activation and for NHEJ, the latter confers nuclease activity (Rotheneder et al, 2023;Käshammer et al, 2019). The MIN motif could in principle disable nucleolytic action by displacing Sae2 from MRN, and counter NHEJ and Tel1 activation by interfering with the 'resting' conformation, possibly in light of its ability to increase the rate of ATP hydrolysis by RAD50 (Roisné-Hamelin et al, 2021;Hailemariam et al, 2019a;Khayat et al, 2021;Marsella et al, 2021;Cassani et al, 2016).…”

“…In addition, MRN is required for activation of the ATM/Tel1 kinase (Hailemariam et al, 2019b; Roset et al, 2014; Lee et al, 2013). In yeast, the MRX complex is additionally required for DSB repair by NHEJ (Boulton and Jackson, 1998; Reis et al, 2012), an activity that has been attributed to the ability of the long coiled-coil stemming from the globular head domain of RAD50 to interact intermolecularly and to promote DNA end-tethering (Rotheneder et al, 2023; Park et al, 2017). Although telomeres suppress the ability of MRN to promote DNA repair, in budding yeast MRX/Tel1 also plays an important role in activating telomerase (Nugent et al, 1998) whilst in human cells ATM can similarly promote telomerase action (Tong et al, 2015; Lee et al, 2015).…”

“…Within the MRN complex, Rad50 fulfils a role as a crucial regulatory subunit, responsible for orchestrating an ATP-driven shift from a ‘resting’ ATP-bound conformation to a ‘cutting’ one that is ADP-bound (Lafrance-Vanasse et al, 2015; Deshpande et al, 2014). While the former is proficient for DNA binding and tethering, as well as for Tel1/ATM activation and for NHEJ, the latter confers nuclease activity (Rotheneder et al, 2023; Käshammer et al, 2019). The MIN motif could in principle disable nucleolytic action by displacing Sae2 from MRN, and counter NHEJ and Tel1 activation by interfering with the ‘resting’ conformation, possibly in light of its ability to increase the rate of ATP hydrolysis by RAD50 (Roisné-Hamelin et al, 2021; Hailemariam et al, 2019a; Khayat et al, 2021; Marsella et al, 2021; Cassani et al, 2016).…”