The Multiple Faces of the MRN Complex: Roles in Medulloblastoma and Beyond

Simple Summary Defects in MRE11A/RAD50/NBS1 (MRN) genes and overexpression of the MRN proteins are both linked to cancer, generating confusion about how the MRN complex impacts cancer initiation and progression. In this review, we examined the most relevant studies on the topic, taking advantage of our recent publication on the role of NBS1 as both a haploinsufficient tumor suppressor and an essential gene in SHH-medulloblastoma. Finally, we discussed the possibility to use genomic and molecular characterization of the MRN complex in clinical practice to improve therapeutic strategies, together with future research directions and challenges. Hypomorphic mutations in MRN complex genes are frequently found in cancer, supporting their role as oncosuppressors. However, unlike canonical oncosuppressors, MRN proteins are often overexpressed in tumor tissues, where they actively work to counteract DSBs induced by both oncogene-dependent RS and radio-chemotherapy. Moreover, at the same time, MRN genes are also essential genes, since the constitutive KO of each component leads to embryonic lethality. Therefore, even though it is paradoxical, MRN genes may work as oncosuppressive, oncopromoting, and essential genes. In this review, we discussed how alterations in the MRN complex impact the physiopathology of cancer, in light of our recent discoveries on the gene-dosage-dependent effect of NBS1 in Medulloblastoma. These updates aim to understand whether MRN complex can be realistically used as a prognostic/predictive marker and/or as a therapeutic target for the treatment of cancer patients in the future.