MRE11 meiotic recombination 11 homolog A (S. cerevisiae)

2004-05-01   Nancy Uhrhammer 

Centre Jean-Perrin, BP 392, 63000 Clermont-Ferrand, France

Identity

HGNC
LOCATION
11q21
LOCUSID
ALIAS
ATLD,HNGS1,MRE11A,MRE11B
FUSION GENES

DNA/RNA

Description

22 exons spanning 76 kb

Transcription

Two isoforms are expressed, isoform 1 at 4772nt; isoform 2, 4688 nt, transcribed from an alternative first (noncoding) exon and lacking exon 5.

Proteins

Description

Both isoforms are approximately 80 kDa. Isoform 1 includes 708 amino acids; isoform 2 includes 680. Molecular studies of Mre11 typically do not distinguish between the different isoforms. Mre11 is a subunit of the Rad50/Mre11/NBS1 (R/M/N) complex and serves as a single-strand DNA endonuclease, a 3 to 5 DNA exonuclease, and to open hairpin DNA structures.

Expression

All tissues examined, with higher levels in proliferating tissues.

Localisation

Nuclear.

Function

Mre11 participates in the repair of DNA double-strand breaks and replication errors as well as in meiotic homologous recombination. The R/M/N complex is part of the BRCA1-associated genome surveillance complex (BASC). The phosphorylation of Mre11 and NBS1 by another member of this super-complex, ATM, is essential for an early step in the response to DNA double-strand breaks (DSBs) and for their repair by either non-homologous end joining (NHEJ) or homologous recombination (HR). The interaction of DNA end-bound Mre11 with Ku70 may direct the break to rejoining by NHEJ, while the absense of Ku70 favors repair by HR. Current models propose DSB detection by R/M/N is required for the activation of ATM, which in turn phosphorylates Mre11 and NBS1, thus placing Mre11 both upstream and downstream of ATM in the DNA damage response signal transduction cascade.

A mechanism has been proposed in which each end of a DNA DSB is bound by an R/M/N dimer, the two dimers being held to each other via the Zinc-hook domain of each Rad50 unit. As the Zinc-hook of Rad50 is located at the end of a long coiled-coil domain, this provides a flexible structure in which each DNA end is accessible to additional repair enzymes while being held in close proximity to each other in preparation for re-ligation.

Cells lacking Mre11 are deficient in DSB repair, and exhibit hypersensitivity to DNA damaging agents such as ionizing radiation and radiomimetic drugs. Such cells also have abnormal DNA replication and high levels of chromosomal instability.

Homology

The gene is conserved throughout eukaryotes, with 70% nucleic acid homology to S. cerevisiea Mre11.

Mutations

Germinal

The hypomorphic arg633ter, asn117ser and arg571ter alleles have been described in ATLD patients. Homozygosity for null alleles is thought to be lethal in embryogenesis, as is the case in Mre11 knockout mice. Germline mutations have also been found in sporadic hematopoetic malignancies, with loss of the wild-type allele in the malignant cells.

Somatic

Rare mutations have been found in breast cancer and lymphoma. In colon cancers not expressing Mre11, the mutation of a poly-T tract in intron 4 has been shown to induce a splicing error that truncates the protein. Seven of 20 gastric tumors failed to express Mre11, although the cause of this was not demonstrated.

Implicated in

Entity name
Ataxia telangiectasia - like disorder (ATLD)
Disease
Ataxia telangiectasia-like disorder is a progressive cerebellar degenerative disease with telangiectasia, immunodeficiency, cancer risk, radiosensitivity, and chromosomal instability. Only a very few ATLD patients are known, in spite of the suggestion that as many as 6% of "A-T" patients may in fact have mutations in Mre11 (this figure is calculated be comparing the size (and thus the opportunity for mutation) of the two genes, as well as the observation that a small minority of A-T patients express apparently normal ATM and for whom no ATM mutation has been detected). The two disorders cannot be distinguished by their phenotypes, though there is some indication that ATLD may have a milder course. The severity of the disease may be dependent on the residual activity of the mutated Mre11 alleles.
Prognosis
Poor, though the course of the disease may be milder than found in classic A-T.
Cytogenetics
Spontaneous chromatid/chromosome breaks; non clonal stable chromosome rearrangements involving immunoglobulin superfamily genes e.g. inv(7)(p14q35); clonal rearrangements.

Bibliography

Pubmed IDLast YearTitleAuthors
115113672001Mre11 protein complex prevents double-strand break accumulation during chromosomal DNA replication.Costanzo V et al
118506212002The DNA damage-dependent intra-S phase checkpoint is regulated by parallel pathways.Falck J et al
111961672001Alterations of the double-strand break repair gene MRE11 in cancer.Fukuda T et al
118503992002Human MRE11 is inactivated in mismatch repair-deficient cancers.Giannini G et al
121520852002The Rad50 zinc-hook is a structure joining Mre11 complexes in DNA recombination and repair.Hopfner KP et al
85301041995Isolation and characterization of the human MRE11 homologue.Petrini JH et al
106123941999The DNA double-strand break repair gene hMRE11 is mutated in individuals with an ataxia-telangiectasia-like disorder.Stewart GS et al
107831652000BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures.Wang Y et al

Other Information

Locus ID:

NCBI: 4361
MIM: 600814
HGNC: 7230
Ensembl: ENSG00000020922

Variants:

dbSNP: 4361
ClinVar: 4361
TCGA: ENSG00000020922
COSMIC: MRE11

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000020922ENST00000323929P49959
ENSG00000020922ENST00000323929A0A024R395
ENSG00000020922ENST00000323977P49959
ENSG00000020922ENST00000393241F8W7U8
ENSG00000020922ENST00000407439P49959
ENSG00000020922ENST00000536754F5H256
ENSG00000020922ENST00000538923F5H742
ENSG00000020922ENST00000540013F5GXT0

Expression (GTEx)

0
5
10
15
20
25

Pathways

PathwaySourceExternal ID
Homologous recombinationKEGGko03440
Non-homologous end-joiningKEGGko03450
Homologous recombinationKEGGhsa03440
Non-homologous end-joiningKEGGhsa03450
MRN complexKEGGhsa_M00291
BRCA1-associated genome surveillance complex (BASC)KEGGhsa_M00295
MRN complexKEGGM00291
BRCA1-associated genome surveillance complex (BASC)KEGGM00295
Immune SystemREACTOMER-HSA-168256
Innate Immune SystemREACTOMER-HSA-168249
Cytosolic sensors of pathogen-associated DNAREACTOMER-HSA-1834949
STING mediated induction of host immune responsesREACTOMER-HSA-1834941
IRF3-mediated induction of type I IFNREACTOMER-HSA-3270619
Gene ExpressionREACTOMER-HSA-74160
Generic Transcription PathwayREACTOMER-HSA-212436
Transcriptional Regulation by TP53REACTOMER-HSA-3700989
Cell CycleREACTOMER-HSA-1640170
Cell Cycle CheckpointsREACTOMER-HSA-69620
G2/M CheckpointsREACTOMER-HSA-69481
G2/M DNA damage checkpointREACTOMER-HSA-69473
MeiosisREACTOMER-HSA-1500620
Meiotic recombinationREACTOMER-HSA-912446
DNA RepairREACTOMER-HSA-73894
Cellular responses to stressREACTOMER-HSA-2262752
Cellular SenescenceREACTOMER-HSA-2559583
DNA Damage/Telomere Stress Induced SenescenceREACTOMER-HSA-2559586
DNA Double-Strand Break RepairREACTOMER-HSA-5693532
DNA Double Strand Break ResponseREACTOMER-HSA-5693606
Sensing of DNA Double Strand BreaksREACTOMER-HSA-5693548
Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksREACTOMER-HSA-5693565
Homology Directed RepairREACTOMER-HSA-5693538
HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA)REACTOMER-HSA-5693567
Processing of DNA double-strand break endsREACTOMER-HSA-5693607
HDR through Homologous Recombination (HRR)REACTOMER-HSA-5685942
Homologous DNA Pairing and Strand ExchangeREACTOMER-HSA-5693579
Presynaptic phase of homologous DNA pairing and strand exchangeREACTOMER-HSA-5693616
Resolution of D-Loop StructuresREACTOMER-HSA-5693537
Resolution of D-loop Structures through Holliday Junction IntermediatesREACTOMER-HSA-5693568
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)REACTOMER-HSA-5693554
HDR through Single Strand Annealing (SSA)REACTOMER-HSA-5685938
HDR through MMEJ (alt-NHEJ)REACTOMER-HSA-5685939
Nonhomologous End-Joining (NHEJ)REACTOMER-HSA-5693571
Regulation of TP53 ActivityREACTOMER-HSA-5633007
Regulation of TP53 Activity through PhosphorylationREACTOMER-HSA-6804756

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
157908082005ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex.514
163277812006ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks.449
215656122011Double-strand break repair-independent role for BRCA2 in blocking stalled replication fork degradation by MRE11.414
213251342011BLM-DNA2-RPA-MRN and EXO1-BLM-RPA-MRN constitute two DNA end resection machineries for human DNA break repair.301
121246282002Adenovirus oncoproteins inactivate the Mre11-Rad50-NBS1 DNA repair complex.246
180250842008PARP1-dependent kinetics of recruitment of MRE11 and NBS1 proteins to multiple DNA damage sites.192
146570322003The Mre11 complex is required for ATM activation and the G2/M checkpoint.187
243162202014DNA double-strand break repair pathway choice is directed by distinct MRE11 nuclease activities.180
196336682009Role of Mre11 in chromosomal nonhomologous end joining in mammalian cells.161
228630072012Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling.155

Citation

Nancy Uhrhammer

MRE11 meiotic recombination 11 homolog A (S. cerevisiae)

Atlas Genet Cytogenet Oncol Haematol. 2004-05-01

Online version: http://atlasgeneticsoncology.org/gene/247/mre11