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

SIMPLE SUMMARY: A DNA double strand break cuts a chromosome in two and is one of the most dangerous forms of DNA damage. Improper repair can lead to various chromosomal re-arrangements that have been detected in almost all cancer cells. A complex of three proteins (MRE11, RAD50, NBS1 or NBN) detects chromosome breaks and orchestrates repair processes. Mutations in these “break sensor” genes have been described in a multitude of cancers. Here, we provide a comprehensive analysis of reported mutations from data deposited on the Catalogue of Somatic Mutations in Cancer (COSMIC) archive. We also undertake an evolutionary analysis of these genes with the aim to understand whether these mutations preferentially accumulate in conserved residues. Interestingly, we find that mutations are overrepresented in evolutionarily conserved residues of RAD50 and NBS1/NBN but not MRE11. ABSTRACT: The MRN complex (MRE11, RAD50, NBS1/NBN) is a DNA double strand break sensor in eukaryotes. The complex directly participates in, or coordinates, several activities at the break such as DNA resection, activation of the DNA damage checkpoint, chromatin remodeling and recruitment of the repair machinery. Mutations in components of the MRN complex have been described in cancer cells for several decades. Using the Catalogue of Somatic Mutations in Cancer (COSMIC) database, we characterized all the reported MRN mutations. This analysis revealed several hotspot frameshift mutations in all three genes that introduce premature stop codons and truncate large regions of the C-termini. We also found through evolutionary analyses that COSMIC mutations are enriched in conserved residues of NBS1/NBN and RAD50 but not in MRE11. Given that all three genes are important to carcinogenesis, we propose these differential enrichment patterns may reflect a more severe pleiotropic role for MRE11.