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MRE11A MRE11 meiotic recombination 11 homolog A (S. cerevisiae)

Written2004-05Nancy Uhrhammer
Centre Jean-Perrin, BP 392, 63000 Clermont-Ferrand, France

(Note : for Links provided by Atlas : click)

Identity

Other namesMRE11
ATLD
HNGS1
HGNC (Hugo) MRE11A
LocusID (NCBI) 4361
Atlas_Id 247
Location 11q21  [Link to chromosome band 11q21]
Location_base_pair Starts at 94150469 and ends at 94227040 bp from pter ( according to hg19-Feb_2009)  [Mapping MRE11A.png]
Fusion genes
(updated 2016)
MRE11A (11q21) / YAP1 (11q22.1)MRE11A (11q21) / ZNF385A (12q13.13)
Note Pseudogenes have been localized to chromosomes 3q25 and 7q11.2-q11.3.

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.

Protein

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

Note
Entity 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

Mre11 protein complex prevents double-strand break accumulation during chromosomal DNA replication.
Costanzo V, Robertson K, Bibikova M, Kim E, Grieco D, Gottesman M, Carroll D, Gautier J
Molecular cell. 2001 ; 8 (1) : 137-147.
PMID 11511367
 
The DNA damage-dependent intra-S phase checkpoint is regulated by parallel pathways.
Falck J, Petrini JH, Williams BR, Lukas J, Bartek J
Nature genetics. 2002 ; 30 (3) : 290-294.
PMID 11850621
 
Isolation and characterization of the human MRE11 homologue.
Petrini JH, Walsh ME, DiMare C, Chen XN, Korenberg JR, Weaver DT
Genomics. 1995 ; 29 (1) : 80-86.
PMID 8530104
 
The DNA double-strand break repair gene hMRE11 is mutated in individuals with an ataxia-telangiectasia-like disorder.
Stewart GS, Maser RS, Stankovic T, Bressan DA, Kaplan MI, Jaspers NG, Raams A, Byrd PJ, Petrini JH, Taylor AM
Cell. 1999 ; 99 (6) : 577-587.
PMID 10612394
 
BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures.
Wang Y, Cortez D, Yazdi P, Neff N, Elledge SJ, Qin J
Genes & development. 2000 ; 14 (8) : 927-939.
PMID 10783165
 
Mutations of an intronic repeat induce impaired MRE11 expression in primary human cancer with microsatellite instability.
Giannini G, Rinaldi C, Ristori E, Ambrosini MI, Cerignoli F, Viel A, Bidoli E, Berni S, D'Amati G, Scambia G, Frati L, Screpanti I, Gulino A
Oncogene. 2004 ; 23 (15) : 2640-2647.
PMID 15048091
 
Human MRE11 is inactivated in mismatch repair-deficient cancers.
Giannini G, Ristori E, Cerignoli F, Rinaldi C, Zani M, Viel A, Ottini L, Crescenzi M, Martinotti S, Bignami M, Frati L, Screpanti I, Gulino A
EMBO reports. 2002 ; 3 (3) : 248-254.
PMID 11850399
 
Alterations of the double-strand break repair gene MRE11 in cancer.
Fukuda T, Sumiyoshi T, Takahashi M, Kataoka T, Asahara T, Inui H, Watatani M, Yasutomi M, Kamada N, Miyagawa K
Cancer research. 2001 ; 61 (1) : 23-26.
PMID 11196167
 
The Rad50 zinc-hook is a structure joining Mre11 complexes in DNA recombination and repair.
Hopfner KP, Craig L, Moncalian G, Zinkel RA, Usui T, Owen BA, Karcher A, Henderson B, Bodmer JL, McMurray CT, Carney JP, Petrini JH, Tainer JA
Nature. 2002 ; 418 (6897) : 562-566.
PMID 12152085
 

Citation

This paper should be referenced as such :
Uhrhammer, N. MRE11A (MRE11 meiotic recombination 11 homolog A (S
cerevisiae))
Atlas Genet Cytogenet Oncol Haematol. 2004;8(3):198-199.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/MRE11ID247.html


External links

Nomenclature
HGNC (Hugo)MRE11A   7230
Cards
AtlasMRE11ID247
Entrez_Gene (NCBI)MRE11A  4361  MRE11 homolog A, double strand break repair nuclease
AliasesATLD; HNGS1; MRE11; MRE11B
GeneCards (Weizmann)MRE11A
Ensembl hg19 (Hinxton)ENSG00000020922 [Gene_View]  chr11:94150469-94227040 [Contig_View]  MRE11A [Vega]
Ensembl hg38 (Hinxton)ENSG00000020922 [Gene_View]  chr11:94150469-94227040 [Contig_View]  MRE11A [Vega]
ICGC DataPortalENSG00000020922
TCGA cBioPortalMRE11A
AceView (NCBI)MRE11A
Genatlas (Paris)MRE11A
WikiGenes4361
SOURCE (Princeton)MRE11A
Genomic and cartography
GoldenPath hg19 (UCSC)MRE11A  -     chr11:94150469-94227040 -  11q21   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)MRE11A  -     11q21   [Description]    (hg38-Dec_2013)
EnsemblMRE11A - 11q21 [CytoView hg19]  MRE11A - 11q21 [CytoView hg38]
Mapping of homologs : NCBIMRE11A [Mapview hg19]  MRE11A [Mapview hg38]
OMIM600814   604391   
Gene and transcription
Genbank (Entrez)AF022778 AF073362 AK095388 AK308318 BC005241
RefSeq transcript (Entrez)NM_005590 NM_005591
RefSeq genomic (Entrez)NC_000011 NC_018922 NG_007261 NT_033899 NW_004929380
Consensus coding sequences : CCDS (NCBI)MRE11A
Cluster EST : UnigeneHs.192649 [ NCBI ]
CGAP (NCI)Hs.192649
Alternative Splicing GalleryENSG00000020922
Gene ExpressionMRE11A [ NCBI-GEO ]   MRE11A [ EBI - ARRAY_EXPRESS ]   MRE11A [ SEEK ]   MRE11A [ MEM ]
Gene Expression Viewer (FireBrowse)MRE11A [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)4361
GTEX Portal (Tissue expression)MRE11A
Protein : pattern, domain, 3D structure
UniProt/SwissProtP49959 (Uniprot)
NextProtP49959  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP49959
Splice isoforms : SwissVarP49959 (Swissvar)
PhosPhoSitePlusP49959
Domains : Interpro (EBI)Calcineurin-like_PHP_apaH    Metallo-depent_PP-like    Mre11    Mre11_DNA-bd   
Domain families : Pfam (Sanger)Metallophos (PF00149)    Mre11_DNA_bind (PF04152)   
Domain families : Pfam (NCBI)pfam00149    pfam04152   
DMDM Disease mutations4361
Blocks (Seattle)MRE11A
PDB (SRS)3T1I   
PDB (PDBSum)3T1I   
PDB (IMB)3T1I   
PDB (RSDB)3T1I   
Structural Biology KnowledgeBase3T1I   
SCOP (Structural Classification of Proteins)3T1I   
CATH (Classification of proteins structures)3T1I   
SuperfamilyP49959
Human Protein AtlasENSG00000020922
Peptide AtlasP49959
HPRD02889
IPIIPI00940798   IPI00218853   IPI00029159   IPI01011534   IPI01012347   IPI01010110   IPI01009648   
Protein Interaction databases
DIP (DOE-UCLA)P49959
IntAct (EBI)P49959
FunCoupENSG00000020922
BioGRIDMRE11A
STRING (EMBL)MRE11A
ZODIACMRE11A
Ontologies - Pathways
QuickGOP49959
Ontology : AmiGOsingle-stranded DNA endodeoxyribonuclease activity  regulation of mitotic recombination  double-strand break repair via homologous recombination  DNA double-strand break processing  DNA synthesis involved in DNA repair  strand displacement  chromosome, telomeric region  nuclear chromosome, telomeric region  nuclear chromosome, telomeric region  nuclear chromosome, telomeric region  nuclear chromatin  condensed nuclear chromosome  DNA binding  double-stranded DNA binding  ATP-dependent DNA helicase activity  nuclease activity  endodeoxyribonuclease activity  endodeoxyribonuclease activity  protein binding  nucleus  nucleoplasm  nucleoplasm  cytosol  DNA replication  DNA repair  double-strand break repair  double-strand break repair via nonhomologous end joining  double-strand break repair via nonhomologous end joining  DNA recombination  cellular response to DNA damage stimulus  telomere maintenance via telomerase  sister chromatid cohesion  mitotic G2 DNA damage checkpoint  synapsis  reciprocal meiotic recombination  heart development  protein C-terminus binding  cell proliferation  3'-5' exonuclease activity  viral process  PML body  PML body  manganese ion binding  Mre11 complex  Mre11 complex  intra-S DNA damage checkpoint  telomeric 3' overhang formation  positive regulation of protein autophosphorylation  positive regulation of telomere maintenance  positive regulation of type I interferon production  DNA duplex unwinding  negative regulation of DNA endoreduplication  positive regulation of kinase activity  site of double-strand break  negative regulation of apoptotic process  negative regulation of viral entry into host cell  perinuclear region of cytoplasm  nucleic acid phosphodiester bond hydrolysis  nucleic acid phosphodiester bond hydrolysis  nucleic acid phosphodiester bond hydrolysis  regulation of signal transduction by p53 class mediator  
Ontology : EGO-EBIsingle-stranded DNA endodeoxyribonuclease activity  regulation of mitotic recombination  double-strand break repair via homologous recombination  DNA double-strand break processing  DNA synthesis involved in DNA repair  strand displacement  chromosome, telomeric region  nuclear chromosome, telomeric region  nuclear chromosome, telomeric region  nuclear chromosome, telomeric region  nuclear chromatin  condensed nuclear chromosome  DNA binding  double-stranded DNA binding  ATP-dependent DNA helicase activity  nuclease activity  endodeoxyribonuclease activity  endodeoxyribonuclease activity  protein binding  nucleus  nucleoplasm  nucleoplasm  cytosol  DNA replication  DNA repair  double-strand break repair  double-strand break repair via nonhomologous end joining  double-strand break repair via nonhomologous end joining  DNA recombination  cellular response to DNA damage stimulus  telomere maintenance via telomerase  sister chromatid cohesion  mitotic G2 DNA damage checkpoint  synapsis  reciprocal meiotic recombination  heart development  protein C-terminus binding  cell proliferation  3'-5' exonuclease activity  viral process  PML body  PML body  manganese ion binding  Mre11 complex  Mre11 complex  intra-S DNA damage checkpoint  telomeric 3' overhang formation  positive regulation of protein autophosphorylation  positive regulation of telomere maintenance  positive regulation of type I interferon production  DNA duplex unwinding  negative regulation of DNA endoreduplication  positive regulation of kinase activity  site of double-strand break  negative regulation of apoptotic process  negative regulation of viral entry into host cell  perinuclear region of cytoplasm  nucleic acid phosphodiester bond hydrolysis  nucleic acid phosphodiester bond hydrolysis  nucleic acid phosphodiester bond hydrolysis  regulation of signal transduction by p53 class mediator  
Pathways : BIOCARTARole of BRCA1, BRCA2 and ATR in Cancer Susceptibility [Genes]    ATM Signaling Pathway [Genes]   
Pathways : KEGGHomologous recombination    Non-homologous end-joining   
REACTOMEP49959 [protein]
REACTOME PathwaysR-HSA-2559586 DNA Damage/Telomere Stress Induced Senescence [pathway]
REACTOME PathwaysR-HSA-912446 Meiotic recombination [pathway]
REACTOME PathwaysR-HSA-69473 G2/M DNA damage checkpoint [pathway]
REACTOME PathwaysR-HSA-1834949 Cytosolic sensors of pathogen-associated DNA [pathway]
REACTOME PathwaysR-HSA-75177 Assembly of the RAD50-MRE11-NBS1 complex at DNA double-strand breaks [pathway]
REACTOME PathwaysR-HSA-3270619 IRF3-mediated induction of type I IFN [pathway]
NDEx Network
Atlas of Cancer Signalling NetworkMRE11A
Wikipedia pathwaysMRE11A
Orthology - Evolution
OrthoDB4361
GeneTree (enSembl)ENSG00000020922
Phylogenetic Trees/Animal Genes : TreeFamMRE11A
Homologs : HomoloGeneMRE11A
Homology/Alignments : Family Browser (UCSC)MRE11A
Gene fusions - Rearrangements
Fusion : MitelmanMRE11A/YAP1 [11q21/11q22.1]  
Fusion: TCGAMRE11A 11q21 YAP1 11q22.1 LGG
Polymorphisms : SNP, variants
NCBI Variation ViewerMRE11A [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)MRE11A
dbVarMRE11A
ClinVarMRE11A
1000_GenomesMRE11A 
Exome Variant ServerMRE11A
ExAC (Exome Aggregation Consortium)MRE11A (select the gene name)
Genetic variants : HAPMAP4361
Genomic Variants (DGV)MRE11A [DGVbeta]
Mutations
ICGC Data PortalMRE11A 
TCGA Data PortalMRE11A 
Broad Tumor PortalMRE11A
OASIS PortalMRE11A [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICMRE11A 
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
LOVD (Leiden Open Variation Database)Zhejiang University Center for Genetic and Genomic Medicine (ZJU-CGGM)
LOVD (Leiden Open Variation Database)**PUBLIC** CCHMC Molecular Genetics Laboratory Mutation Database
BioMutasearch MRE11A
DgiDB (Drug Gene Interaction Database)MRE11A
DoCM (Curated mutations)MRE11A (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)MRE11A (select a term)
intoGenMRE11A
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] 
Diseases
DECIPHER (Syndromes)11:94150469-94227040  ENSG00000020922
CONAN: Copy Number AnalysisMRE11A 
Mutations and Diseases : HGMDMRE11A
OMIM600814    604391   
MedgenMRE11A
Genetic Testing Registry MRE11A
NextProtP49959 [Medical]
TSGene4361
GENETestsMRE11A
Huge Navigator MRE11A [HugePedia]
snp3D : Map Gene to Disease4361
BioCentury BCIQMRE11A
ClinGenMRE11A
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD4361
Chemical/Pharm GKB GenePA30934
Clinical trialMRE11A
Miscellaneous
canSAR (ICR)MRE11A (select the gene name)
Probes
Litterature
PubMed248 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineMRE11A
EVEXMRE11A
GoPubMedMRE11A
iHOPMRE11A
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Sat Jun 11 13:07:56 CEST 2016

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