ATP Hydrolysis by RAD50 Protein Switches MRE11 Enzyme from Endonuclease to Exonuclease

Abstract

Background: RAD50-MRE11-Nbs1 complex is essential for DNA repair. Results: ATP binding by RAD50 closes the complex; MRE11 is an endonuclease. ATP hydrolysis opens the complex; MRE11 is an exonuclease. Conclusion: ATP hydrolysis is a switch converting MRE11 from an endonuclease to an exonuclease. Significance: ATP-dependent nuclease switch provides a mechanism of how RAD50-MRE11 complex is able to coordinate DNA repair.

Structural Studies of DNA End Detection and Resection in Homologous Recombination

“…In this conformation, the two active sites of the Mre11 dimer are blocked, at least for binding of double-stranded DNA (dsDNA). These structural studies are consistent with reports that ATP binding to Rad50 negatively regulates the processive 3 0 dsDNA exonuclease and dsDNA endonuclease activity (but not the ssDNA endonuclease activity) of Mre11 (Herdendorf et al 2011;Lim et al 2011;Majka et al 2012;Deshpande et al 2014). The closed, ATP-bound conformation is also the conformation that activates ATM (Lee et al 2013;Deshpande et al 2014).…”

Repair of Double-Strand Breaks by End Joining

“…3D) ). This changes the disposition of the Rad50 coiled-coils and influences Mre11 nuclease activity, with the open and closed configurations promoting exo-and endonuclease activities, respectively (Majka et al 2012).…”

hMSH5 Facilitates the Repair of Camptothecin-induced Double-strand Breaks through an Interaction with FANCJ

“…To this end, hMSH5 deficiency is expected to strengthen the inhibition of hMRE11 nuclease by FANCJ, whereas concomitant FANCJ deficiency could antagonize this effect. However, this view may be a little simplistic because FANCJ interacts with both hMRE11 and RAD50 in the same complex (39), and the endonuclease and exonuclease activities of MRE11 are also regulated by RAD50-mediated ATP hydrolysis (58). In addition, it is possible that cells deficient in both hMSH5 and FANCJ may survive replication fork collapse by utilizing alternative pathways to activate Chk1.…”