The MRE11 complex: A versatile toolkit for the repair of broken DNA

When DNA breaks, the ends need to be stabilized and processed to facilitate subsequent repair, which can occur by either direct but error-prone end-joining with another broken DNA molecule or a more accurate homology-directed repair by the recombination machinery. At the same time, the presence of broken DNA triggers a signaling cascade that regulates the repair events and cellular progression through the cell cycle. The MRE11 nuclease, together with RAD50 and NBS1 forms a complex termed MRN that participates in all these processes. Although MRE11 was first identified more than 20 years ago, deep insights into its mechanism of action and regulation are much more recent. Here we review how MRE11 functions within MRN, and how the complex is further regulated by CtIP and its phosphorylation in a cell cycle dependent manner. We describe how RAD50, NBS1 and CtIP convert MRE11, exhibiting per se a 3'→5' exonuclease activity, into an ensemble that instead degrades primarily the 5'-terminated strand by endonucleolytic cleavage at DNA break sites to generate 3' overhangs, as required for the initiation of homologous recombination. The unique mechanism of DNA end resection by MRN-CtIP makes it a very flexible toolkit to process DNA breaks with a variety of secondary structures and protein blocks. Such a block can also be the Ku heterodimer, and emerging evidence suggests that MRN-CtIP may often need to remove Ku from DNA ends before initiating homologous recombination. Misregulation of DNA break repair results in mutations and chromosome rearrangements that can drive cancer development. Therefore, a detailed understanding of the underlying processes is highly relevant for human health.