Mre11a, also known as meiotic recombination 11 homolog A, is a 3'-5' exonuclease and endonuclease. It is implicated in multiple DNA repair pathways, including DNA mismatch repair (MMR), homologous recombination repair (HR) for double-strand breaks and replication fork disruption, and is a critical component of the MRN complex [2,4,5,6]. It plays a significant role in maintaining genomic stability and cell homeostasis. Genetic models, such as KO/CKO mouse models, are valuable for studying its functions.

In rheumatoid arthritis (RA), Mre11A deficiency in CD4+ T cells disrupts mitochondrial oxygen consumption, suppresses ATP generation, causes mtDNA leakage into the cytosol, triggers inflammasome assembly, caspase-1 activation, and pyroptotic cell death, leading to tissue inflammation. Conversely, Mre11A overexpression restores mitochondrial fitness and shields tissue from inflammatory attack [1]. In esophageal squamous cell carcinoma (ESCC), suppression of Mre11A expression is associated with cisplatin resistance. UBQLN4 binds to ubiquitinated-Mre11A, increasing its degradation and promoting cisplatin resistance [3]. In colorectal cancer (CRC), high Mre11A transcript abundance is associated with shorter overall survival and a higher risk of death [4]. Knockdown of Mre11A in HeLa cells increases sensitivity to MNNG treatment, DNA damage, and apoptosis, and increases MMR activity, suggesting it negatively regulates MMR [2].

In conclusion, Mre11a is essential for DNA repair, mitochondrial protection, and maintaining tissue homeostasis. Its deficiency is associated with various diseases including RA, ESCC, and CRC. Studies using KO/CKO mouse models have revealed its role in disease-related biological processes, providing insights into potential therapeutic targets for these diseases.