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

Identity

Other namesMRE11
ATLD
HNGS1
HGNC (Hugo) MRE11A
Location 11q21
Location_base_pair Starts at 93790115 and ends at 93866688 bp from pter ( according to hg18-Mar_2006)  [Mapping]
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

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.
  

External links

Nomenclature
HGNC (Hugo)MRE11A   7230
Entrez_Gene (NCBI)MRE11A  4361  MRE11 meiotic recombination 11 homolog A (S. cerevisiae)
Cards
AtlasMRE11ID247
GeneCards (Weizmann)MRE11A
Ensembl (Hinxton)ENSG00000020922 [Gene_View]  MRE11A [Vega]
AceView (NCBI)MRE11A
Genatlas (Paris)MRE11A
euGene (Indiana)4361
SOURCE (Stanford)NM_005590 NM_005591
Gene Expression (Array Express) ENSG00000020922
Genomic and cartography
GoldenPath (UCSC)MRE11A  -  11q21   chr11:93790115-93866688 -  11q21   [Description]    (hg18-Mar_2006)
EnsemblMRE11A - 11q21 [CytoView]
Mapping of homologs : NCBIMRE11A [Mapview]
OMIM600814   604391   
Gene and transcription
Gene : Genbank (Entrez)AF022778 AF073362 AK095388 AK308318 BC005241
Reference sequence (RefSeq transcript) :SRSNM_005590 NM_005591
Reference transcript : EntrezNM_005590 NM_005591
RefSeq genomic : SRSAC_000054 AC_000143 NC_000011 NG_007261 NT_167190 NW_001838042 NW_925173
RefSeq genomic : EntrezAC_000054 AC_000143 NC_000011 NG_007261 NT_167190 NW_001838042 NW_925173
Consensus coding sequences : CCDS NCBIMRE11A
Cluster EST : UnigeneHs.192649 [ SRS ] Hs.192649 [ NCBI ]
Alternative Splicing : Fast-db (Paris)13130
Protein : pattern, domain, 3D structure
Protein : UniProt/SwissProtP49959 (SRS) P49959 (Expasy) P49959 (Uniprot)
With graphics : InterProP49959
Splice isoforms : VarSplice FASTAP49959(VarSplice FASTA)
Domains : Interpro (SRS)DNA_repair    M-pesterase    Mre11_DNA_bd   
Domains : Interpro (EBI)DNA_repair    M-pesterase    Mre11_DNA_bd   
Related proteins : CluSTrP49959
Domain families : Pfam SRSMetallophos (PF00149)    Mre11_DNA_bind (PF04152)   
Domain families : Pfam SangerMetallophos (PF00149)    Mre11_DNA_bind (PF04152)   
Domain families : Pfam NCBIpfam00149    pfam04152   
Blocks (Seattle)P49959
Crystal structure of protein : PDB SRS
Crystal structure of protein : PDBSum
Crystal structure of protein : IMB
Crystal structure of protein : PDB RSDB
HPRD02889
Protein Interaction databases
DIP (DOE-UCLA)P49959
IntAct (EBI)P49959
Polymorphism : SNP, mutations, diseases
Single Nucleotide Polymorphism (SNP) : dbSNP NCBIMRE11A
SNP : GeneSNP UtahMRE11A
SNP : HGBaseMRE11A
Genetic variants : HAPMAPMRE11A
Somatic Mutations in Cancer : COSMICMRE11A 
Mutations and Diseases : HGMDMRE11A
Hereditary diseases : OMIM600814    604391   
Hereditary diseases : GENETests600814    604391   
Diseases : Genetic AssociationMRE11A
General knowledge
Homologs : HomoloGeneMRE11A
Homology/Alignments : Family Browser UCSCMRE11A
Phylogenetic Trees/Animal Genes : TreeFamMRE11A
Chemical/Protein Interactions : CTD4361
Keywords Ontology : AmiGOsingle-stranded DNA specific endodeoxyribonuclease activity  regulation of mitotic recombination  chromosome, telomeric region  DNA binding  double-stranded DNA binding  ATP-dependent DNA helicase activity  nucleus  nucleoplasm  nucleolus  double-strand break repair via nonhomologous end joining  response to DNA damage stimulus  telomere maintenance via telomerase  meiosis  reciprocal meiotic recombination  protein C-terminus binding  3'-5' exonuclease activity  hydrolase activity  manganese ion binding  Mre11 complex  positive regulation of protein amino acid autophosphorylation  DNA duplex unwinding  positive regulation of kinase activity  
Keywords Ontology : EGO-EBIsingle-stranded DNA specific endodeoxyribonuclease activity  regulation of mitotic recombination  chromosome, telomeric region  DNA binding  double-stranded DNA binding  ATP-dependent DNA helicase activity  nucleus  nucleoplasm  nucleolus  double-strand break repair via nonhomologous end joining  response to DNA damage stimulus  telomere maintenance via telomerase  meiosis  reciprocal meiotic recombination  protein C-terminus binding  3'-5' exonuclease activity  hydrolase activity  manganese ion binding  Mre11 complex  positive regulation of protein amino acid autophosphorylation  DNA duplex unwinding  positive regulation of kinase activity  
Pathways : BIOCARTAATM Signaling Pathway [Genes]    Role of BRCA1, BRCA2 and ATR in Cancer Susceptibility [Genes]   
Pathways : KEGG
Other databases
Probes
Probes : ImagenesMRE11A Related clones (RZPD - Berlin)
Literature
PubMed120 Pubmed reference(s) in Entrez
PubGeneMRE11A

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
 
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Contributor(s)

Written05-2004Nancy Uhrhammer

Citation

This paper should be referenced as such :
Uhrhammer N . MRE11A MRE11 meiotic recombination 11 homolog A (S. cerevisiae). Atlas Genet Cytogenet Oncol Haematol. May 2004 .
URL : http://AtlasGeneticsOncology.org/Genes/MRE11ID247.html

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indexed on : Sat Feb 27 10:54:09 CET 2010

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