Double-strand break repair protein MRE11 (Meiotic recombination 11) is an enzyme that in humans is encoded by the MRE11 gene. [5] The gene has been designated MRE11A to distinguish it from the pseudogene MRE11B that is nowadays named MRE11P1.
Double-strand break repair protein MRE11 (Meiotic recombination 11) is an enzyme that in humans is encoded by the MRE11 gene. [5] The gene has been designated MRE11A to distinguish it from the pseudogene MRE11B that is nowadays named MRE11P1.
This gene encodes a nuclear protein involved in homologous recombination, telomere length maintenance, and DNA double-strand break repair. By itself, the protein has 3' to 5' exonuclease activity and endonuclease activity. The protein forms a complex with the RAD50 homolog; this complex is required for nonhomologous joining of DNA ends and possesses increased single-stranded DNA endonuclease and 3' to 5' exonuclease activities. In conjunction with a DNA ligase, this protein promotes the joining of noncomplementary ends in vitro using short homologies near the ends of the DNA fragments. This gene has a pseudogene on chromosome 3. Alternative splicing of this gene results in two transcript variants encoding different isoforms. [6]
Mre11, an ortholog of human MRE11, occurs in the prokaryote archaeon Sulfolobus acidocaldarius . [7] In this organism the Mre11 protein interacts with the Rad50 protein and appears to have an active role in the repair of DNA damages experimentally introduced by gamma radiation. [7] Similarly, during meiosis in the eukaryotic protist Tetrahymena Mre11 is required for repair of DNA damages, in this case double-strand breaks, [8] by a process that likely involves homologous recombination. These observations suggest that human MRE11 is descended from prokaryotic and protist ancestral Mre11 proteins that served a role in early processes for repairing DNA damage.
MRE11 has a role in microhomology-mediated end joining (MMEJ) repair of double strand breaks. It is one of 6 enzymes required for this error prone DNA repair pathway. [9] MRE11 is over-expressed in breast cancers. [10]
Cancers are very often deficient in expression of one or more DNA repair genes, but over-expression of a DNA repair gene is less usual in cancer. For instance, at least 36 DNA repair enzymes, when mutationally defective in germ line cells, cause increased risk of cancer (hereditary cancer syndromes).[ citation needed ] (Also see DNA repair-deficiency disorder.) Similarly, at least 12 DNA repair genes have frequently been found to be epigenetically repressed in one or more cancers.[ citation needed ] (See also Epigenetically reduced DNA repair and cancer.) Ordinarily, deficient expression of a DNA repair enzyme results in increased un-repaired DNA damages which, through replication errors (translesion synthesis), lead to mutations and cancer. However, MRE11 mediated MMEJ repair is highly inaccurate, so in this case, over-expression, rather than under-expression, apparently leads to cancer.
MRE11 has been shown to interact with:
Breast cancer type 1 susceptibility protein is a protein that in humans is encoded by the BRCA1 gene. Orthologs are common in other vertebrate species, whereas invertebrate genomes may encode a more distantly related gene. BRCA1 is a human tumor suppressor gene and is responsible for repairing DNA.
BRCA2 and BRCA2 are human genes and their protein products, respectively. The official symbol and the official name are maintained by the HUGO Gene Nomenclature Committee. One alternative symbol, FANCD1, recognizes its association with the FANC protein complex. Orthologs, styled Brca2 and Brca2, are common in other vertebrate species. BRCA2 is a human tumor suppressor gene, found in all humans; its protein, also called by the synonym breast cancer type 2 susceptibility protein, is responsible for repairing DNA.
Non-homologous end joining (NHEJ) is a pathway that repairs double-strand breaks in DNA. It is called "non-homologous" because the break ends are directly ligated without the need for a homologous template, in contrast to homology directed repair (HDR), which requires a homologous sequence to guide repair. NHEJ is active in both non-dividing and proliferating cells, while HDR is not readily accessible in non-dividing cells. The term "non-homologous end joining" was coined in 1996 by Moore and Haber.
ATM serine/threonine kinase or Ataxia-telangiectasia mutated, symbol ATM, is a serine/threonine protein kinase that is recruited and activated by DNA double-strand breaks, oxidative stress, topoisomerase cleavage complexes, splicing intermediates, R-loops and in some cases by single-strand DNA breaks. It phosphorylates several key proteins that initiate activation of the DNA damage checkpoint, leading to cell cycle arrest, DNA repair or apoptosis. Several of these targets, including p53, CHK2, BRCA1, NBS1 and H2AX are tumor suppressors.
Nijmegen breakage syndrome (NBS) is a rare autosomal recessive congenital disorder causing chromosomal instability, probably as a result of a defect in the double Holliday junction DNA repair mechanism and/or the synthesis dependent strand annealing mechanism for repairing double strand breaks in DNA.
Serine/threonine-protein kinase ATR, also known as ataxia telangiectasia and Rad3-related protein (ATR) or FRAP-related protein 1 (FRP1), is an enzyme that, in humans, is encoded by the ATR gene. It is a large kinase of about 301.66 kDa. ATR belongs to the phosphatidylinositol 3-kinase-related kinase protein family. ATR is activated in response to single strand breaks, and works with ATM to ensure genome integrity.
Nibrin, also known as NBN or NBS1, is a protein which in humans is encoded by the NBN gene.
H2A histone family member X is a type of histone protein from the H2A family encoded by the H2AFX gene. An important phosphorylated form is γH2AX (S139), which forms when double-strand breaks appear.
BRCA1-associated RING domain protein 1 is a protein that in humans is encoded by the BARD1 gene. The human BARD1 protein is 777 amino acids long and contains a RING finger domain, four ankyrin repeats, and two tandem BRCT domains.
Telomeric repeat-binding factor 2 is a protein that is present at telomeres throughout the cell cycle. It is also known as TERF2, TRF2, and TRBF2, and is encoded in humans by the TERF2 gene. It is a component of the shelterin nucleoprotein complex and a second negative regulator of telomere length, playing a key role in the protective activity of telomeres. It was first reported in 1997 in the lab of Titia de Lange, where a DNA sequence similar, but not identical, to TERF1 was discovered, with respect to the Myb-domain. De Lange isolated the new Myb-containing protein sequence and called it TERF2.
Cell cycle checkpoint protein RAD17 is a protein that in humans is encoded by the RAD17 gene.
Bloom syndrome protein is a protein that in humans is encoded by the BLM gene and is not expressed in Bloom syndrome.
DNA repair protein RAD50, also known as RAD50, is a protein that in humans is encoded by the RAD50 gene.
RAD52 homolog , also known as RAD52, is a protein which in humans is encoded by the RAD52 gene.
Mediator of DNA damage checkpoint protein 1 is a 2080 amino acid long protein that in humans is encoded by the MDC1 gene located on the short arm (p) of chromosome 6. MDC1 protein is a regulator of the Intra-S phase and the G2/M cell cycle checkpoints and recruits repair proteins to the site of DNA damage. It is involved in determining cell survival fate in association with tumor suppressor protein p53. This protein also goes by the name Nuclear Factor with BRCT Domain 1 (NFBD1).
DNA repair protein XRCC2 is a protein that in humans is encoded by the XRCC2 gene.
SAE2 is a gene in budding yeast, coding for the protein Sae2, which is involved in DNA repair. Sae2 is a part of the homologous recombination process in response to double-strand breaks. It is best characterized in the yeast model organism Saccharomyces cerevisiae. Homologous genes in other organisms include Ctp1 in fission yeast, Com1 in plants, and CtIP in higher eukaryotes including humans.
Telomeric repeat-binding factor 2-interacting protein 1 also known as repressor activator protein 1 (Rap1) is a protein that in humans is encoded by the TERF2IP gene.
E3 ubiquitin-protein ligase RNF8 is an enzyme that in humans is encoded by the RNF8 gene. RNF8 has activity both in immune system functions and in DNA repair.
The MRN complex is a protein complex consisting of Mre11, Rad50 and Nbs1. In eukaryotes, the MRN/X complex plays an important role in the initial processing of double-strand DNA breaks prior to repair by homologous recombination or non-homologous end joining. The MRN complex binds avidly to double-strand breaks both in vitro and in vivo and may serve to tether broken ends prior to repair by non-homologous end joining or to initiate DNA end resection prior to repair by homologous recombination. The MRN complex also participates in activating the checkpoint kinase ATM in response to DNA damage. Production of short single-strand oligonucleotides by Mre11 endonuclease activity has been implicated in ATM activation by the MRN complex.