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.

Differences in PARP Inhibitors for the Treatment of Ovarian Cancer: Mechanisms of Action, Pharmacology, Safety, and Efficacy

“…Furthermore, PARP is able to act on the DSB repair pathway [ 18 ] through the modulation of the enzymes MRE11 and NBS1, which are key factors of another important pathway of DNA repair, which is homologous recombination (HR) [ 19 , 20 , 21 ]. In addition, PARP regulates RAD51 genes through Fbh1 dependent and interacts with and poly-ADP-ribosylates (also known as PARsylates) BRCA1.…”

Mutation Spectra of the MRN (MRE11, RAD50, NBS1/NBN) Break Sensor in Cancer Cells

“…Some of the other NBS1/NBN mutations have also been described previously [ 56 ]. The E185Q mutation is a common polymorphism that occurs in breast, prostate, lung, and several other cancers [ 59 , 102 , 103 , 104 ]. The significance of synonymous mutations is debatable, but studies suggest that they may affect mRNA stability and therefore could lead to changes in gene expression [ 66 , 105 ].…”

“…Several frameshift mutation of MRE11, RAD50 and NBS1 have been independently identified by various studies [56] or detected in large cancer mutation screens ( Supplementary Table S1) but to our knowledge the fact that N511Ifs * 13, K722Rfs*14, R466Gfs*18, R551Gfs*8 form hotspots have not been shown. A recent report cataloging disease associated MRN mutations also does not list them [59]. The MRE11 N511fs*13 (c.1532del) [69][70][71][72][73][74][75][76] Several frameshift mutation of MRE11, RAD50 and NBS1 have been independently identified by various studies [56] or detected in large cancer mutation screens ( Supplementary Table S1) but to our knowledge the fact that N511Ifs*13, K722Rfs*14, R466Gfs*18, R551Gfs*8 form hotspots have not been shown.…”

“…The MRE11 N511fs*13 (c.1532del) [69][70][71][72][73][74][75][76] Several frameshift mutation of MRE11, RAD50 and NBS1 have been independently identified by various studies [56] or detected in large cancer mutation screens ( Supplementary Table S1) but to our knowledge the fact that N511Ifs*13, K722Rfs*14, R466Gfs*18, R551Gfs*8 form hotspots have not been shown. A recent report cataloging disease associated MRN mutations also does not list them [59]. The MRE11 N511fs*13 (c.1532del) [69][70][71][72][73][74][75][76] position always produces the same frameshift signature.…”

“…These undesirable chromosome products are hallmarks of cancer cells [ 57 ]. Several diseases directly linked to MRN mutations such as the Nijmegen Breakage Syndrome have been identified and are reviewed elsewhere [ 56 , 58 , 59 ]. Additionally, many cancer cells are characterized by MRN mutations ranging from amino acid substitution to complete deletion of the gene [ 56 ].…”