A Survey of Reported Disease-Related Mutations in the MRE11-RAD50-NBS1 Complex

Abstract

The MRE11-RAD50-NBS1 (MRN) protein complex is one of the primary vehicles for repairing DNA double strand breaks and maintaining the genomic stability within the cell. The role of the MRN complex to recognize and process DNA double-strand breaks as well as signal other damage response factors is critical for maintaining proper cellular function. Mutations in any one of the components of the MRN complex that effect function or expression of the repair machinery could be detrimental to the cell and may initiate and/or propagate disease. Here, we discuss, in a structural and biochemical context, mutations in each of the three MRN components that have been associated with diseases such as ataxia telangiectasia-like disorder (ATLD), Nijmegen breakage syndrome (NBS), NBS-like disorder (NBSLD) and certain types of cancers. Overall, deepening our understanding of disease-causing mutations of the MRN complex at the structural and biochemical level is foundational to the future aim of treating diseases associated with these aberrations.

Keywords: ATLD; DNA double-strand break repair; MRE11-RAD50-NBS1; NBS; cancer mutations.

Figure 1

Global conformational changes in the MRN complex induced by ATP binding and hydrolysis. Cartoon representation of MRE11 (blue shades), RAD50 (red and light green), and NBS1 (orange shades). Each monomer in the MRE11 dimer is bound to a RAD50 and NBS1. ATP binding to RAD50 causes RAD50 monomers to associate creating a “closed” complex. Subsequent ATP hydrolysis and ADP + P_i release allows the complex to return to an “open” state.

Figure 2

Disease-associated mutations in MRE11. Top, domain architecture of MRE11. The numbers below indicate the position of mutations outlined in the text and in Table 1. Red, green, and blue numbers correspond to mutations associated with cancer, ATLD, and NBSLD, respectively. The two arrows above indicate the position of the NBS1 interacting regions. Bottom, crystal structure of the MRE11 nuclease and capping domain dimer from C. thermophilum (PDB ID: 4YKE). Since the helix-loop-helix and GAR domains are absent in this structure, they are cartooned in (not to scale).

Figure 3

Disease-associated mutations in RAD50. Top, domain architecture of RAD50. The numbers indicate the position of mutations outlined in the text and Table 2. Red and blue numbers correspond to mutations associated with cancer and NBSLD, respectively. The two arrows above indicate the positions where MRE11 binds. Bottom, crystal structures of the dimer RAD50 nucleotide binding domain in complex with the MRE11 helix-loop-helix domain from C. thermophilum (PDB ID: 5DA9) and the dimer zinc hook domain from H. sapiens (PDB ID: 5GOX). This is the ATPγS-bound “closed” conformation of Rad50. The majority of the coiled-coil domain is absent from these structures, so it is was cartooned in to connect the two structures and is not to scale.

Figure 4

Disease-associated mutations in NBS1. Top, domain architecture of NBS1. The numbers indicate the position of mutations outlined in the text and in Table 3. Red and gold numbers correspond to mutations associated with cancer and NBS, respectively. The two arrows above indicate the positions where MRE11 and ATM bind. Bottom, crystal structure of the S. pombe FHA and tandem BRCT domains (PDB ID: 3HUE). The intrinsically disordered C-terminus is cartooned in and is not to scale.