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MRN and the race to the break

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Abstract

In all living cells, DNA is constantly threatened by both endogenous and exogenous agents. In order to protect genetic information, all cells have developed a sophisticated network of proteins, which constantly monitor genomic integrity. This network, termed the DNA damage response, senses and signals the presence of DNA damage to effect numerous biological responses, including DNA repair, transient cell cycle arrests (“checkpoints”) and apoptosis. The MRN complex (MRX in yeast), composed of Mre11, Rad50 and Nbs1 (Xrs2), is a key component of the immediate early response to DNA damage, involved in a cross-talk between the repair and checkpoint machinery. Using its ability to bind DNA ends, it is ideally placed to sense and signal the presence of double strand breaks and plays an important role in DNA repair and cellular survival. Here, we summarise recent observation on MRN structure, function, regulation and emerging mechanisms by which the MRN nano-machinery protects genomic integrity. Finally, we discuss the biological significance of the unique MRN structure and summarise the emerging sequence of early events of the response to double strand breaks orchestrated by the MRN complex.

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Acknowledgements

The authors thank Sunichi Takeda for his authorisation to cite unpublished results, Serge Gravel and Karl Peter Hopfner for critical reading of the manuscript and John Eykelenboom for his comments. The work in Noel Lowndes laboratory is supported by Cancer Research Ireland under grant CR105GRE, European Commission Integrated project “DNA Repair” contract number 512113 and Science Foundation Ireland Principal Investigator award 07/IN1/B958.

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  1. Centre for Chromosome Biology, School of Natural Science, National University of Ireland Galway, University Road, Galway, Ireland

    Agnieszka Rupnik, Noel F. Lowndes & Muriel Grenon

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  1. Agnieszka Rupnik
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  2. Noel F. Lowndes
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  3. Muriel Grenon
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Correspondence to Noel F. Lowndes or Muriel Grenon.

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During the preparation of these proofs, two articles have been published describing the NBS1 crystal structure of both FHA domain and BRCT repeats of human and S. pombe cells. The results presented in these publications suggest an important role in phospheptide binding for both of these domains. Scott Williams et al. Cell, 139 (1) 87–99, Nbs1 Flexibly Tethers Ctp1 and Mre11-Rad50 to Coordinate DNA Double-Strand Break Processing and Repair Lloyd et al. Cell, 139 (1) 100–111, A Supramodular FHA/BRCT-Repeat Architecture Mediates Nbs1 Adaptor Function in Response to DNA Damage.

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Rupnik, A., Lowndes, N.F. & Grenon, M. MRN and the race to the break. Chromosoma 119, 115–135 (2010). https://doi.org/10.1007/s00412-009-0242-4

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