MRN complex

In eukaryotes, the MRN/X complex plays an important role in the initial processing of double-strand DNA breaks prior to repair by homologous recombination or non-homologous end joining.

[6] Similarly, during meiosis in the eukaryotic protist Tetrahymena Mre11 is required for repair of DNA damages, in this case double-strand breaks,[7] by a process that likely involves homologous recombination.

[21] All three disorders belong to a group of chromosomal instability syndromes that are associated with impaired DNA damage response and increased cellular sensitivity to ionising radiation.

Double-strand DNA breaks, which it monitors and signals for repair, may themselves be the cause of carcinogenic genetic alteration,[23] suggesting MRN provides a protective effect during normal cell homeostasis.

Extension studies have confirmed an increase in B and T-cell lymphomas in Nbs1-mutated mice in conjunction with p53 suppression, indicating potential p53 inactivation in lymphomagenesis,[26] which occurs more often in NBS patients.

Similarly, overexpression of Nbs1 in human head and neck squamous cell carcinoma (HNSCC) samples has been shown to induce epithelial–mesenchymal transition (EMT), which itself plays a critical role in cancer metastasis.

The MRN complex has also been implicated in several pathways contributing to the insensitivity of cancer stem cells to the DNA damaging effects of chemotherapy and radiation treatment,[35] which is a source of overall tumor aggression.

[36] The loss of this checkpoint strips cancer stem cells' ability to repair lethal genetic lesions, making them vulnerable to DNA damaging therapeutic agents.

Likewise, overexpression of Nbs1 in HNSCC cells has been correlated with increased activation of the PI3K/AKT pathway, which itself has been shown to contribute to tumor aggression by reducing apoptosis.

[37] Overall, cancer cells appear to rely on MRN's signaling and repair capabilities in response to DNA damage in order to achieve resistance to modern chemo- and radiation therapies.