MRE11A

MRE11 functions as a member of the MRE11-RAD50-NBS1 (MRN) complex in mammals (or the MRE11-RAD50-XRS2 (MRX) complex in yeast). MRE11 is a DNA nuclease involved in multiple DNA double-strand break repair pathways, including homologous recombination,^[6] classical non-homologous end joining,^[7][8][9] and alternative non-homologous end joining.^{[7][8][9][10]} MRE11 activity also facilitates replication fork restart^[11][12] and telomere length maintenance. It also is essential for embryonic development^[13][14] and required for hematopoiesis and lymphopoiesis in mice.^[15] By itself, the protein has 3' to 5' exonuclease activity and endonuclease activity, which is stimulated when complexed with RAD50.^[16][17] CtIP/SAE2 is also known to stimulate MRE11 endonuclease activity to initiate homologous recombination^[18][19][20] or to process blocked DNA ends, such as the removal of SPO11 during meiosis,^[21][22] DNA-PKcs and Ku in mitotic cells,^[23][24][25] or other DNA-protein adducts such as topoisomerase cleavage complexes.^[26][27][28] In conjunction with a DNA ligase, this protein promotes the joining of noncomplementary ends in vitro using short stretches of homology 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.^[29]

Mre11, an ortholog of human MRE11, occurs in the prokaryote archaeon Sulfolobus acidocaldarius.^[30] 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.^[30] Similarly, during meiosis in the eukaryotic protist Tetrahymena Mre11 is required for repair of DNA damages, in this case double-strand breaks,^[31] 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.^[32] MRE11 is over-expressed in breast cancers.^[33]

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:

• ATM,^[34][35]
• BRCA1,^{[35][36][37][38]}
• Ku70,^[39]
• MDC1,^[40]
• NBN,^{[35][17][41][42][43]}
• Rad50,^{[35][36][39][17][44]}
• TERF2,^[45]
• CtIP/SAE2,^[46]
• CDK2,^[47] and
• MRNIP.^[48]

• Homologous recombination