The MRN complex: coordinating and mediating the response to broken chromosomes - PubMed (original) (raw)

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The MRN complex: coordinating and mediating the response to broken chromosomes

Michael van den Bosch et al. EMBO Rep. 2003 Sep.

Abstract

The MRE11-RAD50-NBS1 (MRN) protein complex has been linked to many DNA metabolic events that involve DNA double-stranded breaks (DSBs). In vertebrate cells, all three components are encoded by essential genes, and hypomorphic mutations in any of the human genes can result in genome-instability syndromes. MRN is one of the first factors to be localized to the DNA lesion, where it might initially have a structural role by tethering together, and therefore stabilizing, broken chromosomes. This suggests that MRN could function as a lesion-specific sensor. As well as binding to DNA, MRN has other roles in both the processing and assembly of large macromolecular complexes (known as foci) that facilitate efficient DSB responses. Recently, a novel mediator protein, mediator of DNA damage checkpoint protein 1 (MDC1), was shown to co-immunoprecipitate with the MRN complex and regulate MRE11 foci formation. However, whether the initial recruitment of MRN to DSBs requires MDC1 is unclear. Here, we focus on recent developments in MRN research and propose a model for how DSBs are sensed and the cellular responses to them are mediated.

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Figures

Figure 1

Figure 1

The human MRE11–RAD50–NBS1 complex. (A) The MRE11, RAD50 and NBS1 proteins. Known structural domains for each protein are indicated. Amino termini are to the left. (B) The structure of the MRE11–RAD50–NBS1 (MRN) complex. The MRN complex binds to DNA ends through the MRE11 protein, with the coiled-coil arms of RAD50 extending outwards and interacting with an MRN complex on the other side of the break through their Cys-X-X-Cys (CXXC) motifs. Two MRN complexes are shown for clarity, but many MRN molecules are thought to cluster around the DSB. The many intermolecular interactions between the RAD50 arms are collectively referred to as 'molecular Velcro' (de Jager et al., 2001). A and B, Walker A and B motifs, respectively; aa, amino acids; BRCT, BRCA1 carboxy-terminal domain; FHA, fork-head-associated domain.

Figure 2

Figure 2

The human ATM, γ-H2AX and mediator proteins. Key molecules involved in the double-stranded-break (DSB) response. Known structural domains for each protein are indicated. The ATM and RAD3-related (ATR)-related region in ATM is of unknown function. 53BP1, p53-binding protein 1; ATM, ataxia telangiectasia mutated; BRCA1, breast-cancer-associated protein 1; BRCT, BRCA1 carboxy terminal; FAT, FRAP/ATM/TRRAP; FATC, FAT carboxy terminal; FHA, fork-head associated; MDC1, mediator of DNA damage checkpoint protein 1; PI(3) kinase, phosphatidylinositol-3-OH kinase.

Figure 3

Figure 3

Model of the double-stranded-break response cycle. (A) Undamaged section of a chromosome, showing two chromatin loops and an inactive ATM dimer. (B,C) Induction of a DNA double-stranded break (DSB), modification of chromatin, activation of ATM and recruitment of both ATM and MRE11/RAD50/NBS1 (MRN). The possibility that MRN binds before ATM is shown, but the exact order of events is unknown. The thin black line indicates modified chromatin. (D,E) A wave of H2AX phosphorylation is followed by recruitment of mediators (mediator of DNA damage checkpoint protein 1 (MDC1), p53-binding protein 1 (53BP1) and breast-cancer-associated protein 1 (BRCA1)) to the growing focus, and their ATM-dependent phosphorylation. The molecular architecture of the focus is unknown. (F) Disassembly of the focus, ATM inactivation and chromatin remodelling. The model suggests at least two distinct forms of soluble ATM: an inactive oligomer and an active monomer, and at least two distinct active, insoluble forms: one directly at the lesion and another integral to the growing focus. Note that the MRN complex is also a component of the growing focus but, for clarity, has been omitted here. Complex, persistent lesions are thought to be more difficult to repair, and this is reflected in the size attained by the growing focus. See text for further details. The inset contains a colour-coded key to the molecules shown.

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