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

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. EMBO reports 4, 844-849 (2003) doi:10.1038/sj.embor.embor925 IntroductionDNA damage, such as double-stranded breaks (DSBs), poses a considerable threat to genomic integrity and cell survival. DSBs arise spontaneously during normal DNA processing (for example, during DNA replication and meiosis) and can be induced by a variety of DNAdamaging agents (for example, cancer therapeutic agents such as ionizing radiation (IR) and bleomycin). Checkpoint signalling pathways are required to initially sense the DSB, to amplify this signal and to transduce it to produce the appropriate biological responses. These responses include the induction of a transcriptional programme, the prevention of entry into S phase (the G1/S checkpoint), the slowing of ongoing DNA synthesis (the intra-S checkpoint), the triggering of checkpoints in the G2 and M phases and, in the presence of low to moderate amounts of DNA damage, the enhancement of repair mechanisms by modification and activation of specific repair factors. Alternatively, if the damage is irreparable or an excessive number of lesions is present, checkpoint signalling is also required to induce apoptotic cell death. The two main mechanisms of DSB repair are non-homologous end joining (NHEJ) and homologous recombination (HR; Barnes, 2001;van den Bosch et al., 2002). The malfunction of these mechanisms can result in the fusion of DNA ends that were originally distant from one another in the genome, which generates chromosomal rearrangements such as inversions, translocations and deletions. The resulting disruption of gene expression can perturb normal cell proliferation or result in cell death. The MRN complex and the repair of DNA damageThe highly conserved MRE11-RAD50-NBS1 (MRN) complex is thought to have a key role in the sensing, processing and repair of DSBs, and orthologues of MRE11 and RAD50 are found in all taxonomic kingdoms. The MRE11 protein has amin...

Sodium tungstate modulates ATM function upon DNA damage

“…The MRN complex binds DSB soon after they are formed implicating it in DNA damage detection [38], thus acting upstream ATM and allowing its activation. The complex can tether linear duplex molecules [39], and it is able to bridge broken DNA ends or sister chromatids [40]. MRN function is complex as it also acts downstream of ATM to facilitate the phosphorylation of numerous substrates including Smc1 and Chk2 [3].…”

Structure of a Second BRCT Domain Identified in the Nijmegen Breakage Syndrome Protein Nbs1 and its Function in an MDC1-Dependent Localization of Nbs1 to DNA Damage Sites

“…10,11 MRN is known to play a key role in sensing DNA strand breaks and then amplifying initial signal and transducing it to downstream effector proteins that regulate cell cycle checkpoint and DNA repair. [12][13][14][15] In the MRN complex, Nbs1 regulates the catalytic nucleotide-dependent DNA binding and ATP-dependent DNA unwinding functions of Mre11 and Rad50. 16,17 It is also required for the localization of Mre11 and Rad50 into the nucleus as well as for the activation of ataxia-telangiectasia mutated (ATM) kinase.…”

β-lapachone Activates a Mre11p-Tel1p G1/S Checkpoint in Budding Yeast

“…12 This complex regulates two different DSB repair processes: homologous recombination and non-homologous end joining. 13 In addition, the XMR complex mediates cell responses to DNA damaging agents.…”