MRN complex

The MRN complex (MRX complex in yeast) is a protein complex consisting of Mre11, Rad50 and Nbs1 (also known as Nibrin in humans and as Xrs2 in yeast). 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. The MRN complex binds avidly to double-strand breaks both in vitro and in vivo and may serve to tether broken ends prior to repair by non-homologous end joining or to initiate resection prior to repair by homologous recombination. The MRN complex also participates in activating the checkpoint kinase ATM in response to DNA damage. Production of short single-strand oligonucleotides by Mre11 endonuclease activity has been implicated in ATM activation by the MRN complex.

The MRN complex has been mainly studied in eukaryotes. However, recent work shows that two of the three protein components of this complex, Mre11 and Rad50, are also conserved in extant prokaryotic archaea. This finding suggests that key components of the eukaryotic MRN complex are derived by evolutionary descent from the archaea. In the archaeon Sulfolobus acidocaldarius, the Mre11 protein interacts with the Rad50 protein and appears to have an active role in the repair of DNA damages experimentally introduced by gamma radiation. Similarly, during meiosis in the eukaryotic protist Tetrahymena Mre11 is required for repair of DNA damages, in this case double-strand breaks, by a process that likely involves homologous recombination.

In eukaryotes, the MRN complex (through cooperation of its subunits) has been identified as a crucial player in many stages of the repair process of double-strand DNA breaks: initial detection of a lesion, halting of the cell cycle to allow for repair, selection of a specific repair pathway (i.e., via homologous recombination or non-homologous end joining) and providing mechanisms for initiating reconstruction of the DNA molecule (primarily via spatial juxtaposition of the ends of broken chromosomes). Initial detection is thought to be controlled by both Nbs1 and MRE11. Likewise, cell cycle checkpoint regulation is ultimately controlled by phosphorylation activity of the ATM kinase, which is pathway dependent on both Nbs1 and MRE11. MRE11 alone is known to contribute to repair pathway selection, while MRE11 and Rad50 work together to spatially align DNA molecules: Rad50 tethers two linear DNA molecules together while MRE11 fine-tunes the alignment by binding to the ends of the broken chromosomes.

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