DNA Repair Mechanisms, Protein Interactions and Therapeutic Targeting of the MRN Complex.

Repair of a DNA double-strand break relies upon a pathway of proteins to identify damage, regulate cell cycle checkpoints, and repair the damage. This process is initiated by a sensor protein complex, the MRN complex, comprised of three proteins-MRE11, RAD50, and NBS1. After a double-stranded break, the MRN complex recruits and activates ATM, in-turn activating other proteins such as BRCA1/2, ATR, CHEK1/2, PALB2 and RAD51. These proteins have been the focus of many studies for their individual roles in hereditary cancer syndromes and are included on several genetic testing panels. These panels have enabled us to acquire large amounts of genetic data, much of which remains a challenge to interpret due to the presence of variants of uncertain significance (VUS). While the primary aim of clinical testing is to accurately and confidently classify variants in order to inform medical management, the presence of VUSs has led to ambiguity in genetic counseling. Pathogenic variants within MRN complex genes have been implicated in breast, ovarian, prostate, colon cancers and gliomas; however, the hundreds of VUSs within MRE11, RAD50, and NBS1 precludes the application of these data in genetic guidance of carriers. In this review, we discuss the MRN complex's role in DNA double-strand break repair, its interactions with other cancer predisposing genes, the variants that can be found within the three MRN complex genes, and the MRN complex's potential as an anti-cancer therapeutic target.

Functional analysis of ATM variants in a high risk cohort provides insight into missing heritability.

Variants of unknown significance (VUS) remain a constant challenge in the diagnosis of hereditary cancer and the counseling of patients with pedigrees suggestive of such a syndrome. In order to assess some of this limitation, several variants in the DNA repair gene ATM were selected from a cohort of high risk individuals with negative genetic diagnoses. ATM has proven a challenge in the counseling of patients due to its nature as a moderate penetrance gene. In this study, six ATM missense mutations with a high likelihood for pathogenicity were assessed through a battery of experiments to yield high fidelity information on their biochemical effect on ATM activity. We report that several of these variants show signs of reduced ATM function indicative of likely pathogenicity. With further study, this data may be used in clinic, improving diagnosis, surveillance, and outcome for patients carrying these mutations.