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

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.