Alternative titles; symbols
HGNC Approved Gene Symbol: MRE11
Cytogenetic location: 11q21 Genomic coordinates (GRCh38): 11:94,415,570-94,512,412 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q21 | Ataxia-telangiectasia-like disorder 1 | 604391 | Autosomal recessive | 3 |
Mutation of the Saccharomyces cerevisiae RAD52 (600392) epistasis group gene, MRE11, blocks meiotic recombination, confers profound sensitivity to double-strand break damage, and has a hyperrecombinational phenotype in mitotic cells. Petrini et al. (1995) isolated a highly conserved human MRE11 homolog using a 2-hybrid screen for DNA ligase I-interacting proteins. Human MRE11 shares approximately 50% identity with its yeast counterpart over the N-terminal half of the protein. MRE11 is expressed at highest levels in proliferating tissues but is also observed in other tissues.
Paull and Gellert (1998) found that MRE11 by itself has 3-prime to 5-prime exonuclease activity that is increased when MRE11 is in a complex with RAD50 (604040). MRE11 also exhibits endonuclease activity, as shown by the asymmetric opening of DNA hairpin loops. In conjunction with a DNA ligase, MRE11 promotes the joining of noncomplementary ends in vitro by utilizing short homologies near the ends of the DNA fragments. Sequence identities of 1 to 5 basepairs are present at all of these junctions, and their diversity is consistent with the products of nonhomologous end-joining observed in vivo.
Trujillo et al. (1998) isolated a mammalian cell nuclear complex containing RAD50, MRE11, and nibrin, or p95 (NBS1; 602667), the protein encoded by the gene mutated in Nijmegen breakage syndrome (NBS; 251260). The RAD50 complex possessed manganese-dependent single-stranded DNA endonuclease and 3-prime to 5-prime exonuclease activities. The authors stated that these nuclease activities are likely to be important for recombination, repair, and genomic stability.
Carney et al. (1998) demonstrated that p95 is an integral member of the MRE11/RAD50 complex and that the function of this complex is impaired in cells from NBS patients.
Zhong et al. (1999) demonstrated association of BRCA1 (113705) with the RAD50/MRE11/p95 complex. Upon irradiation, BRCA1 was detected in the nucleus, in discrete foci which colocalized with RAD50. Formation of irradiation-induced foci positive for BRCA1, RAD50, MRE11, or p95 was dramatically reduced in HCC/1937 breast cancer cells carrying a homozygous mutation in BRCA1 but was restored by transfection of wildtype BRCA1. Ectopic expression of wildtype, but not mutated, BRCA1 in these cells rendered them less sensitive to the DNA damage agent methyl methanesulfonate. These data suggested to the authors that BRCA1 is important for the cellular responses to DNA damage that are mediated by the RAD50-MRE11-p95 complex.
Wang et al. (2000) used immunoprecipitation and mass spectrometry analyses to identify BRCA1-associated proteins. They found that BRCA1 is part of a large multisubunit protein complex of tumor suppressors, DNA damage sensors, and signal transducers. They named this complex BASC, for 'BRCA1-associated genome surveillance complex.' Among the DNA repair proteins identified in the complex were ATM (607585), BLM (604610), MSH2 (609309), MSH6 (600678), MLH1 (120436), the RAD50-MRE11-NBS1 complex, and the RFC1 (102579)-RFC2 (600404)-RFC4 (102577) complex. Confocal microscopy demonstrated that BRCA1, BLM, and the RAD50-MRE11-NBS1 complex colocalize to large nuclear foci. Wang et al. (2000) suggested that BASC may serve as a sensor of abnormal DNA structures and/or as a regulator of the postreplication repair process.
Double-strand DNA breaks (DSBs) pose a major threat to living cells, and several mechanisms for repairing these lesions have evolved. Eukaryotes can process DSBs by homologous recombination (HR) on nonhomologous end joining (NHEJ). NHEJ connects DNA ends irrespective of their sequence, and it predominates in mitotic cells, particularly during G1 (Takata et al., 1998). HR requires interaction of the broken DNA molecule with an intact homologous copy, and allows restoration of the original DNA sequence. HR is active during G2 of the mitotic cycle and predominates during meiosis, when the cell creates DSBs, which must be repaired by HR to ensure proper chromosome segregation. How the cell controls the choice between the 2 repair pathways was investigated by Goedecke et al. (1999). They demonstrated a physical interaction between the mammalian Ku70 (152690), which is essential for NHEJ (Baumann and West, 1998), and MRE11, which functions both in NHEJ and meiotic HR. Moreover, they showed that irradiated cells deficient for Ku70 are incapable of targeting Mre11 to subnuclear foci that may represent DNA-repair complexes. Nevertheless, Ku70 and Mre11 were differentially expressed during meiosis. In the mouse testis, Mre11 and Ku70 colocalized in nuclei of somatic cells and in the XY bivalent. In early meiotic prophase, however, when meiotic recombination is most probably initiated, Mre11 was abundant, whereas Ku70 was not detectable. Goedecke et al. (1999) proposed that Ku70 acts as a switch between the 2 DSB repair pathways. When present, Ku70 destines DSBs for NHEJ by binding to DNA ends and attracting other factors for NHEJ, including Mre11; when absent, it allows participation of DNA ends and Mre11 in the meiotic HR pathway.
Zhu et al. (2000) showed by coimmunoprecipitation studies that a small fraction of RAD50, MRE11, and p95 is associated with the telomeric repeat-binding factor TRF2 (602027). Indirect immunofluorescence demonstrated the presence of RAD50 and MRE11 at interphase telomeres. Although the MRE11 complex accumulated in irradiation-induced foci (IRIFs) in response to gamma-irradiation, TRF2 did not relocate to IRIFs and irradiation did not affect the association of TRF2 with the MRE11 complex, arguing against a role for TRF2 in double-strand break repair. Zhu et al. (2000) proposed that the MRE11 complex functions at telomeres, possibly by modulating t-loop formation.
Costanzo et al. (2001) cloned Xenopus Mre11 and studied its role in DNA replication and DNA damage checkpoint in cell-free extracts. DSBs stimulated the phosphorylation and 3-prime-to-5-prime exonuclease activity of the Mre11 complex. This induced phosphorylation was ATM independent. Phosphorylated Mre11 was found associated with replicating nuclei. The Mre11 complex was required to yield normal DNA replication products. Genomic DNA replicated in extracts immunodepleted of Mre11 complex accumulated DSBs, as demonstrated by TUNEL assay and reactivity to phosphorylated histone H2AX (601772) antibodies. In contrast, the ATM-dependent DNA damage checkpoint that blocks DNA replication initiation was Mre11 independent. These results suggested that the function of the Xenopus Mre11 complex is to repair DSBs that arise during normal DNA replication, thus unraveling a critical link between recombination-dependent repair and DNA replication.
Falck et al. (2002) demonstrated that experimental blockade of either the NBS1-MRE11 function or the CHK2 (604373)-triggered events leads to a partial radioresistant DNA synthesis phenotype in human cells. In contrast, concomitant interference with NBS1-MRE11 and the CHK2-CDC25A (116947)-CDK2 (116953) pathways entirely abolishes inhibition of DNA synthesis induced by ionizing radiation, resulting in complete radioresistant DNA synthesis analogous to that caused by defective ATM. In addition, CDK2-dependent loading of CDC45 (603465) onto replication origins, a prerequisite for recruitment of DNA polymerase, was prevented upon irradiation of normal or NBS1/MRE11-defective cells but not cells with defective ATM. Falck et al. (2002) concluded that in response to ionizing radiation, phosphorylation of NBS1 and CHK2 by ATM triggers 2 parallel branches of the DNA damage-dependent S-phase checkpoint that cooperate by inhibiting distinct steps of DNA replication.
In mammalian cells, a conserved multiprotein complex of MRE11, RAD50, and NBS1 (MRN) is important for double-strand break repair, meiotic recombination, and telomere maintenance. In the absence of the early region E4, the double-stranded genome of adenoviruses is joined into concatemers too large to be packaged. Stracker et al. (2002) investigated the cellular proteins involved in the concatemer formation and how they are inactivated by E4 products during a wildtype infection. They demonstrated that concatemerization requires functional MRE11 and NBS1, and that these proteins are found at foci adjacent to viral replication centers. Infection with wildtype virus results in both reorganization and degradation of members of the MRN complex. These activities are mediated by 3 viral oncoproteins that prevent concatemerization. This targeting of cellular proteins involved in the genomic stability suggested a mechanism for 'hit-and-run' transformation observed for these viral oncoproteins.
Franchitto and Pichierri (2002) reviewed the roles of RECQL2 (604611) and RECQL3 (604610) in resolution of a stall in DNA replication, as well as their possible interaction with the MRN complex.
Boisvert et al. (2005) found that PRMT1 (HRMT1L2; 602950) arginine methylated MRE11 in HeLa cells. Mutation of the arginines within the GAR domain of MRE11 severely impaired the exonuclease activity of MRE11 but did not influence its ability to form a complex with RAD50 and NBS1. Inhibition of MRE11 methylation resulted in S-phase checkpoint defects, which were rescued by the MRE11-RAD50-NBS1 complex. Boisvert et al. (2005) concluded that arginine methylation regulates the activity of the MRE11-RAD50-NBS1 complex during the intra-S-phase DNA damage checkpoint response.
Larson et al. (2005) found that MRE11 associated specifically with rearranged Ig genes in hypermutating B cells, whereas APE1 (APEX; 107748), the major apurinic/apyrimidinic (AP) endonuclease in faithful base excision repair, did not. Purified recombinant MRE11/RAD50 cleaved DNA at AP sites within single-stranded regions of DNA, suggesting that at transcribed Ig genes, cleavage may be coordinated with deamination by AID (AICDA; 605257) and deglycosylation by UNG2 (607752) to produce the single-stranded breaks that undergo subsequent mutagenic repair and recombination.
Zhong et al. (2005) tested whether the MRN complex has a global controlling role over ATR (601215) through the study of MRN deficiencies generated by RNA interference. The MRN complex was required for ATR-dependent phosphorylation of SMC1A (300040), which acts within chromatin to ensure sister chromatid cohesion and to effect several DNA damage responses. Novel phenotypes caused by MRN deficiency that support a functional link between this complex, ATR, and SMC1A, included hypersensitivity to UV exposure, a defective UV responsive intra-S phase checkpoint, and a specific pattern of genomic instability. Zhong et al. (2005) concluded that there is a controlling role for the MRN complex over the ATR kinase, and that downstream events under this control are broad, including both chromatin-associated and diffuse signaling factors.
Deng et al. (2009) addressed the question of whether the mammalian MRN complex promotes repair at dysfunctional telomeres, by using mouse alleles that either inactivated the entire MRN complex or eliminated only the nuclease activities of MRE11. Deng et al. (2009) found that cells lacking MRN did not activate ATM when telomeric repeat binding factor-2 (TRF2; 602027) was removed from telomeres, and ligase-4 (LIG4; 601837)-dependent chromosome end-to-end fusions were markedly reduced. Residual chromatid fusions involve only telomeres generated by leading strand synthesis. Notably, although cells deficient for MRE11 nuclease activity efficiently activated ATM and recruited 53BP1 (605230) to deprotected telomeres, the 3-prime telomeric overhang persisted to prevent nonhomologous end joining (NHEJ)-mediated chromosomal fusions. Removal of shelterin proteins that protect the 3-prime overhang in the setting of MRE11 nuclease deficiency restored LIG4-dependent chromosome fusions. Deng et al. (2009) concluded that their data indicated a critical role for the MRN complex in sensing dysfunctional telomeres, and showed that in the absence of TRF2, MRE11 nuclease activity removes the 3-prime telomeric overhang to promote chromosome fusions. MRE11 can also protect newly replicated leading strand telomeres from NHEJ by promoting 5-prime strand resection to generate POT1a (see 606478)-TPP1 (607998)-bound 3-prime overhangs.
Garcia et al. (2011) used Saccharomyces cerevisiae to reveal a role for the Mre11 exonuclease during the resection of Spo11 (605114)-linked 5-prime DNA termini in vivo. They showed that the residual resection observed in Exo1 (606063)-mutant cells is dependent on Mre11, and that both exonuclease activities are required for efficient double-strand break repair. Previous work had indicated that resection traverses unidirectionally. Using a combination of physical assays for 5-prime-end processing, Garcia et al. (2011) observed results indicating an alternative mechanism involving bidirectional resection. First, Mre11 nicks the strand to be resected up to 300 nucleotides from the 5-prime terminus of the double-strand break, much further away than previously assumed. Second, this nick enables resection in a bidirectional manner, using Exo1 in the 5-prime-to-3-prime direction away from the double-strand break, and Mre11 in the 3-prime-to-5-prime direction towards the double-strand break end. Mre11 exonuclease activity also confers resistance to DNA damage in cycling cells, suggesting that Mre11-catalyzed resection may be a general feature of various DNA repair pathways.
Staples et al. (2016) found that human cells depleted of MRNIP (617154) showed increased DNA damage. Immunoprecipitation analysis revealed interaction of MRNIP with the MRN complex, as well as with other substrates of ATM. Cells lacking MRNIP had reduced MRN function and defective ATM-dependent DNA damage signaling, as well as impaired responses to DNA breaks. Staples et al. (2016) concluded that MRNIP, through its interaction with the MRN complex, is required for robust cellular responses to DNA breaks by promoting chromatin association of the MRN complex and subsequent activation of the ATM-signaling cascade.
Kanakkanthara et al. (2016) found that mutant mice that cannot elevate cyclin A2 (123835) are chromosomally unstable and tumor-prone. Underlying the chromosomal instability is a failure to upregulate the Mre11 nuclease in S phase, which leads to impaired resolution of stalled replication forks, insufficient repair of double-stranded DNA breaks, and improper segregation of sister chromosomes. Unexpectedly, cyclin A2 controlled Mre11 abundance through a C-terminal RNA binding domain that selectively and directly binds Mre11 transcripts to mediate polysome loading and translation. Kanakkanthara et al. (2016) concluded that their data revealed cyclin A2 as a mechanistically diverse regulator of DNA replication combining multifaceted kinase-dependent functions with a kinase-independent, RNA binding-dependent role that ensures adequate repair of common replication errors.
Using knockout screens, Cho et al. (2024) identified Mre11 as a DNA damage response gene that suppressed tumorigenesis in a mouse model of breast cancer driven by Myc (190080) overexpression, Cas9 expression, and Tp53 deficiency through regulation of cGas (613973) activation. Binding of the MRN complex to nucleosome fragments was required to displace cGas from acidic patch-mediated sequestration, which enabled its mobilization and activation by double-stranded DNA (dsDNA). Mre11 was therefore essential for cGas activation in response to oncogenic stress, cytosolic dsDNA, and ionizing radiation. Furthermore, Mre11-dependent cGas activation promoted Zbp1 (606750)-Ripk3 (605817)-Mlkl (615153)-mediated necroptosis, which was essential to suppress oncogenic proliferation and breast tumorigenesis. Downregulation of ZBP1 in human triple-negative breast cancer was associated with increased genome instability, immune suppression, and poor patient prognosis. The findings established MRE11 as a crucial mediator that linked DNA damage and cGAS activation, resulting in tumor suppression through ZBP1-dependent necroptosis.
To clarify functions of the MRE11/RAD50 complex in DNA double-strand break repair, Hopfner et al. (2001) reported P. furiosus Mre11 crystal structures, which revealed a protein phosphatase-like dimanganese-binding domain capped by a unique domain that controls active site access. These structures unify the multiple nuclease activities of Mre11 in a single endo/exonuclease mechanism. Mapping human and yeast MRE11 mutations revealed eukaryotic macromolecular interaction sites. Furthermore, the structure of the P. furiosus Rad50 ABC-ATPase with its adjacent coiled-coil defines a compact Mre11/Rad50-ATPase complex and suggests that RAD50-ATP-driven conformational switching directly controls the MRE11 exonuclease. Electron microscopy, small-angle x-ray scattering, and ultracentrifugation data of human and P. furiosus MRE11/RAD50 complex revealed a dual functional complex consisting of a (MRE11)2/(RAD50)2 heterotetrameric DNA-processing head and a double coiled-coil linker.
The human RAD50/MRE11/NBS1 complex (R/M/N) has a dynamic molecular architecture consisting of a globular DNA binding domain from which two 50-nanometer coiled coils protrude. The coiled coils are flexible and their apices can self-associate. The flexibility of the coiled coils allows their apices to adopt an orientation favorable for interaction. However, this also allows interaction between the tips of the 2 coiled coils within the same complex, which competes with and frustrates the intercomplex interaction required for DNA tethering. Moreno-Herrero et al. (2005) showed that the dynamic architecture of the R/M/N complex is markedly affected by DNA binding. DNA binding by the R/M/N globular domain leads to parallel orientation of the coiled coils; this prevents intracomplex interactions and favors intercomplex associations needed for DNA tethering. The R/M/N complex thus is an example of a biologic nanomachine in which binding to its ligand, in this case DNA, affects the functional conformation of a domain located 50 nanometers distant.
By analysis of somatic cell hybrids and by fluorescence in situ hybridization, Petrini et al. (1995) mapped the MRE11 gene to 11q21. An MRE11-related locus was found on 7q11.2-q11.3.
In 2 families with ataxia-telangiectasia-like disorder-1 (ATLD1; 604391), Stewart et al. (1999) identified mutations in the MRE11A gene (600814.0001-600814.0002). Consistent with the clinical outcome of these mutations, cells established from the affected individuals within the 2 families exhibited many of the features characteristic of both ataxia-telangiectasia (208900) and NBS, including chromosomal instability, increased sensitivity to ionizing radiation, defective induction of stress-activated signal transduction pathways, and radioresistant DNA synthesis. These data strengthened the molecular connection between double-stranded break recognition by the MRE11A/RAD50 (604040)/NBS1 (602667) protein complex and the ability of the cell to activate the DNA damage-response pathway controlled by ATM (607585).
Delia et al. (2004) described 2 sibs with late-onset cerebellar degeneration, absence of telangiectasia, and absence of malignancy through their fourth decade. Both patients were compound heterozygotes for MRE11 mutations (600814.0003 and 600814.0004). Lymphoblastoid cell lines (LCLs) derived from these sibs exhibited normal ATM expression, but were defective for MRE11, RAD50, and NBS1 protein expression. Response to gamma-radiation was abnormal, as evident by the enhanced radiosensitivity, attenuated autophosphorylation of serine-1981 on ATM and phosphorylation of serine-15 on p53 (191170) and serine-966 on SMC1A, failure to form Mre11 nuclear foci, and defective G1 checkpoint arrest. Fibroblasts from the 2 sibs, but not LCLs, showed impaired ATM-dependent Chk2 (CHEK2; 604373) phosphorylation.
Fernet et al. (2005) described 10 patients from 3 unrelated Saudi Arabian families with ATLD1. All patients were homozygous for a W210C mutation (600814.0005) in the MRE11A gene. In fibroblast cultures established from 2 individuals, there were high constitutive levels of MRE11A and RAD50 proteins compared with controls but a very low level of the NBS1 protein. After exposure to ionizing radiation, a dose-dependent defect in ATM serine-1981, p53 serine-15 and Chek2 phosphorylation, and p53 stabilization were noted, together with a failure to form MRE11A foci and enhanced radiation sensitivity. Fernet et al. (2005) hypothesized that the MRE11A/RAD50/NBS1 complex may act as a sensor of DNA double-strand breaks, acting upstream of ATM.
In 2 first cousins with ataxia-telangiectasia-like disorder-1 (ATLD1; 604391) from a large inbred family from Pakistan originally reported by Hernandez et al. (1993), Stewart et al. (1999) identified a homozygous C-to-T transition at nucleotide 1897 of the MRE11A gene, resulting in an arg633-to-ter (R633X) mutation. Both patients had progressive cerebellar degeneration, but neither patient showed any intellectual impairment.
Chaki et al. (2012) identified a homozygous R633X mutation in 2 sibs, born of consanguineous Pakistani parents, with ataxia and cerebellar vermis hypoplasia. One patient had dysarthria and myoclonus. Although the patients were part of a larger group of patients with nephronophthisis (see, e.g., NPHP1, 256100) and related ciliopathies, neither had renal failure or retinal involvement. The mutation was found by homozygosity mapping and whole-exome sequencing. The report linked the pathogenesis of NPHP and ciliopathy to defects in DNA damage response signaling.
In 2 brothers with ataxia-telangiectasia-like disorder-1 (ATLD1; 604391) originally reported by Klein et al. (1996), Stewart et al. (1999) identified a heterozygous A-to-G transition at nucleotide 350 of the MRE11A gene, resulting in an asn117-to-ser (N117S) substitution on the paternal allele. No maternally derived mutation was detected by DNA sequencing, suggesting that the mother was heterozygous for a null MRE11A mutation. Western blotting showed reduced MRE11A levels in maternally-derived cells. The boys had early-childhood onset of progressive cerebellar degeneration causing cerebellar ataxia and oculomotor apraxia, but no telangiectasia. Pitts et al. (2001) later identified a heterozygous truncating mutation in the MRE11A gene (600814.0003) on the maternal allele. The findings confirmed autosomal recessive inheritance of the disorder.
In affected members of the family with ataxia-telangiectasia-like disorder-1 (ATLD1; 604391) originally reported by Klein et al. (1996), in whom Stewart et al. (1999) had identified a heterozygous missense mutation in the MRE11A gene (600814.0002) on the paternal allele, Pitts et al. (2001) identified a heterozygous 1714C-T transition in exon 15 of the MRE11A gene, resulting in an arg571-to-ter (R571X) substitution on the maternal allele. This maternally inherited mutant allele had not been detected previously because transcripts derived from it underwent nonsense-mediated mRNA decay.
Delia et al. (2004) described 2 Italian sibs with late-onset cerebellar degeneration that progressed slowly until puberty, absence of telangiectasia, and absence of malignancy through their fourth decade (ATLD1; 604391). In both sibs, the authors identified compound heterozygosity for the R571X mutation (600814.0003) and a 1422C-A transversion in exon 15 of the MRE11A gene, resulting in a thr481-to-lys (T481K) substitution. The T481K mutation was maternally inherited, and the paternal R571X allele was null as a result of NMD.
In 10 patients from 3 unrelated Saudi Arabian families with ataxia-telangiectasia-like disorder-1 (ATLD1; 604391), Fernet et al. (2005) identified homozygosity for a 630G-C transversion in exon 7 of the MRE11A gene, resulting in a trp210-to-cys (W210C) substitution between motifs III and IV of the N-terminal nuclease domain. Patients presented with an early-onset, slowly progressive, ataxia plus ocular apraxia phenotype with an absence of tumor development, even in the oldest 37-year-old patient. Extraneurologic features, such as telangiectasia, raised alpha-fetoprotein, and reduced immunoglobulin levels, were absent.
In a 52-year-old Japanese woman, born of consanguineous parents, with ataxia-telangiectasia-like disorder-1 (ATLD1; 604391), Miyamoto et al. (2014) identified a homozygous c.140C-T transition in the MRE11A gene, resulting in an ala47-to-val (A47V) substitution in the highly conserved nuclease domain. The mutation, which was found by a combination of linkage analysis and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was filtered against the dbSNP (build 135), 1000 Genomes Project, and Exome Sequencing Project databases, and was not found in 174 control individuals. Western blot analysis of patient cells showed mildly decreased levels of MRE11A, RAD50 (604040), and NBS1 (NBN; 602667) that likely did not fully disrupt the MRN complex. The patient had a relatively mild disease course: she presented with subcortical myoclonus at age 9 years, and developed ataxia in her forties. Brain imaging did not show cerebellar atrophy.
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