Double-strand break repair protein MRE11 (MRE11A)

The protein contains 708 amino acids for an estimated molecular weight of 80593 Da.

 

Component of the MRN complex, which plays a central role in double-strand break (DSB) repair, DNA recombination, maintenance of telomere integrity and meiosis (PubMed:9651580, PubMed:9590181, PubMed:9705271, PubMed:11741547, PubMed:29670289). The complex possesses single-strand endonuclease activity and double-strand-specific 3'-5' exonuclease activity, which are provided by MRE11 (PubMed:9651580, PubMed:9590181, PubMed:9705271, PubMed:11741547, PubMed:29670289). RAD50 may be required to bind DNA ends and hold them in close proximity (PubMed:9651580, PubMed:9590181, PubMed:9705271, PubMed:11741547, PubMed:29670289). This could facilitate searches for short or long regions of sequence homology in the recombining DNA templates, and may also stimulate the activity of DNA ligases and/or restrict the nuclease activity of MRE11 to prevent nucleolytic degradation past a given point (PubMed:9651580, PubMed:9590181, PubMed:9705271, PubMed:11741547, PubMed:29670289, PubMed:30612738). The complex may also be required for DNA damage signaling via activation of the ATM kinase (PubMed:15064416). In telomeres the MRN complex may modulate t-loop formation (PubMed:10888888). (updated: May 8, 2019)

Protein identification was indicated in the following studies:

  1. Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
  2. Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
  3. Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
  4. Wilson and co-workers. (2016) Comparison of the Proteome of Adult and Cord Erythroid Cells, and Changes in the Proteome Following Reticulocyte Maturation. Mol Cell Proteomics. 15(6), 1938-1946.
  5. Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
  6. D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
  7. Chu and co-workers. (2018) Quantitative mass spectrometry of human reticulocytes reveal proteome-wide modifications during maturation. Br J Haematol. 180(1), 118-133.

Methods

The following articles were analysed to gather the proteome content of erythrocytes.

The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.

PublicationIdentification 1Uniprot mapping 2Not mapped /
Obsolete
TrEMBLSwiss-Prot
Goodman (2013)2289 (gene list)227853205992269
Lange (2014)123412347281224
Hegedus (2015)2638262202352387
Wilson (2016)165815281702911068
d'Alessandro (2017)18261817201815
Bryk (2017)20902060101081942
Chu (2018)18531804553621387

1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry

The compilation of older studies can be retrieved from the Red Blood Cell Collection database.

The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.

No sequence conservation computed yet.

Interpro domains
Total structural coverage: 58%
Model score: 34

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VariantDescription
cancer
ATLD1
dbSNP:rs147771140
a breast cancer sample; somatic mutation
a breast cancer sample; somatic mutation
ovarian cancer
dbSNP:rs1805367
cancer
cancer
dbSNP:rs1805362

The reference OMIM entry for this protein is 600814

Meiotic recombination 11, s. cerevisiae, homolog of, a; mre11a
Mre11

CLONING

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.

GENE FUNCTION

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 f ... More on the omim web site

Subscribe to this protein entry history

May 11, 2019: Protein entry updated
Automatic update: Entry updated from uniprot information.

Feb. 10, 2018: Protein entry updated
Automatic update: Entry updated from uniprot information.

Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated

Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated

Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated

March 16, 2016: Protein entry updated
Automatic update: OMIM entry 600814 was added.

Jan. 24, 2016: Protein entry updated
Automatic update: model status changed