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The MRE11 complex: starting from the ends

Key Points

  • The MRE11 complex, consisting of meiotic recombination 11 (MRE11), RAD50 and Nijmegen breakage syndrome 1 (NBS1; also known as nibrin), is of key importance in the DNA damage response to DNA double-strand breaks, and therefore regulates genome stability.

  • The MRE11 complex regulates repair of DNA double-strand breaks in several contexts, including replication, telomere homeostasis, meiosis, apoptosis and immune system development.

  • Structural studies of the MRE11 complex have provided insights into the distinct roles that different components in this complex have. The globular domain of the MRE11 complex is important for DNA binding, the RAD50 hook domain mediates complex homodimerization and NBS1 mediates regulation of the complex.

  • Mouse models for different alleles of the MRE11 complex have been developed on the basis of these structural studies, and show clinical features of the human syndromes that the MRE11 complex has been linked to.

Abstract

The maintenance of genome stability depends on the DNA damage response (DDR), which is a functional network comprising signal transduction, cell cycle regulation and DNA repair. The metabolism of DNA double-strand breaks governed by the DDR is important for preventing genomic alterations and sporadic cancers, and hereditary defects in this response cause debilitating human pathologies, including developmental defects and cancer. The MRE11 complex, composed of the meiotic recombination 11 (MRE11), RAD50 and Nijmegen breakage syndrome 1 (NBS1; also known as nibrin) proteins is central to the DDR, and recent insights into its structure and function have been gained from in vitro structural analysis and studies of animal models in which the DDR response is deficient.

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Figure 1: The MRE11 complex regulates the mammalian DNA damage response.
Figure 2: The MRE11 complex consists of a globular domain and extended coiled-coils.
Figure 3: The MRE11 complex controls telomere homeostasis.
Figure 4: The MRE11 complex in human disease and mouse models.

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Acknowledgements

J.H.J.P. is supported by grants from the US National Institutes of Health, the Geoffrey Beene Foundation and the Goodwin Foundation. T.H.S. is a Ramon y Cajal investigator and is supported by grants from the Ministerio de Ciencia e Innovación, Spain. We are grateful to M. Hohl for providing data and help with figures, members of our laboratories for insightful discussions, and F. Moreno-Herrero, C. Wyman and R. Kanaar for scanning force microscopy images. We apologize to our many colleagues whose important work could not be described owing to space limitations and the focus of the Review.

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Correspondence to Travis H. Stracker or John H. J. Petrini.

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DATABASES

Mouse Genome Informatics

Mre11a tm1Dof

Mre11a tm2.1Dof

Mre11a tm2.2Dof

Mre11a tm1Jpt

Nbn tm1Jpt

Nbn tm2.1Jpt

Nbn tm3Jpt

Nbn tm1Md

Nbn tm1.1Md

Nbn tm2Nus

Nbn tm1Xu

Nbn tm1Zqw

Nbn tm2Zqw

Rad50 tm1Jpt

Rad50 tm2Jpt

Rad50 tm3Jpt

Pfam

PF04423

FURTHER INFORMATION

Travis H. Stracker's homepage

John H. J. Petrini's homepage

SUPPLEMENTARY INFORMATION

S1 (table)

Glossary

Cytotoxic response

A cellular response to stimuli leading to cell death.

Cytostatic response

A cellular response to stimuli leading to a suppression of cell growth.

Topoisomerase poison

A class of drugs used in cancer therapy that trap covalent intermediates of topoisomerases, causing DNA damage that is exacerbated by DNA replication.

Clastogenic cancer therapy

A type of cancer therapy that relies on a clastogen, or DNA break-inducing agent, to target proliferating cells in tumours.

Ataxia

A neurological condition characterized by loss of motor control. This often results from defects in the development or degeneration of the cerebellum.

Homology directed repair

A major double-strand break repair pathway that is template-mediated and therefore considered to be highly accurate. Particularly important for sister chromatid regulation in S/G2 phase.

Non-homologous end-joining

A major double-strand break repair pathway that involves the ligation of free ends, sometimes after processing that leads to the loss or gain of sequence. This pathway is particularly well studied in the context of V(D)J recombination.

Alternative non-homologous end-joining

A poorly characterized end-joining pathway (or pathways) that is not dependent on the core non-homologous end-joining components. This pathway frequently uses short microhomologies (5–25 nucleotides) and is thought to be resection dependent.

Sister chromatids

Identical chromatids that are joined by a centromere and generated during S phase DNA replication.

Resection

The process of converting double-stranded DNA to single-stranded DNA by the exonucleolytic removal of one strand. Resection is often performed in conjunction with the action of a helicase and is implicated in both the checkpoint activation and multiple repair pathways.

Scanning force microscopy

A type of microscopy that uses a physical probe to scan the surfaces of a specimen and provide high-resolution images at a nanoscale level. Also known as atomic force microscopy.

Endonuclease

An enzyme that cleaves the phosphodiester bond of DNA within a polynucleotide chain.

Exonuclease

An enzyme that cleaves the phosphodiester bond of DNA from the end of a polynucleotide chain.

Zinc finger domain

A protein structural motif that coordinates zinc ions via Cys and His residues to stabilize folds involved in nucleic acid or protein binding.

FKBP domain

A domain originally found in the FK506-binding protein (FKBP) that mediates its interactions with the immunosuppressant FK506. Binding of FK506 or analogues leads to dimerization and is used as an inducible artificial dimerization domain in fusion proteins.

Isosteric mutant

An amino acid substitution that approximates the spatial and chemical properties of the residue that it replaces.

BRCA1 C-terminal domain

A phosphopeptide-binding domain first identified in the carboxyl terminus of the breast cancer associated 1 (BRCA1) protein. These domains are usually found in tandem.

Methyl methanesulphonate

A carcinogenic alkylating agent that generates strand breaks and is used in cancer therapy.

Microcephaly

A neurodevelopmental disorder characterized by reduced head circumference and often accompanied by neurological problems including mental retardation and delayed development of motor functions.

Hypomorphic allele

An allele that results in a partial loss of function.

Hypermorphic allele

An allele that results in a partial gain of function or increased activity.

Class switch recombination

The process by which B cells change the production of antibody from one class (or isotype) to another. This involves the exchange of constant and variable regions and involves the induction and repair of DNA double-strand breaks. Also known as isotype switching.

V(D)J recombination

A process that assembles diverse immunoglobulin and T-cell receptor genes from existing variable (V), diversity (D) and joining (J) gene segments. V(D)J recombination is initiated by the RAG1–RAG2 recombinase in a sequence-specific manner. Also known as antigen receptor gene rearrangement.

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Stracker, T., Petrini, J. The MRE11 complex: starting from the ends. Nat Rev Mol Cell Biol 12, 90–103 (2011). https://doi.org/10.1038/nrm3047

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