SUMMARY PARAGRAPH for MRE11
Identified in separate screens for mutants sensitive to ionizing radiation and alkylating agents and defective in meiotic recombination, MRE11 is a member of the RAD52 epistasis group (8 and references therein, 9, 7). Other members of this group include RAD50, RAD51, RAD52, RAD54, RDH54, RAD55, RAD57, RAD59, and XRS2. All members of the RAD52 epistasis group are involved in the repair of double-stranded breaks (DSBs) in DNA. Mutants are defective in the repair of DNA damage caused by ionizing radiation and the alkylating agent methyl methanesulfonate (MMS), in the maintenance of telomere length, in mitotic and meiotic recombination, and in mating-type switching because DSB intermediates are involved in these processes (reviewed in 10 and 11).
Mre11p, Rad50p, and Xrs2p comprise the Mre11 complex. Mre11p/Rad50p/Xrs2p (MRX or RMX) association is stable with a predicted stoichiometry of 2:2:1, however, Rad50p and Xrs2p do not interact in the absence of Mre11p (12, 13). Complex functions include DNA binding, exonuclease and endonuclease activities, DNA unwinding, and DNA end recognition (14, 15, 16). In addition to the repair processes listed above, which are mostly dependent upon homologous recombination, the MRX complex also facilitates DSB repair via nonhomologous end-joining as well as introduction of DSBs in meiosis, detection of damaged DNA, DNA damage checkpoint activation, telomerase recruitment, and suppression of gross chromosomal rearrangements (reviewed in 10 and 11).
The Mre11 complex is conserved structurally and functionally from archaea to humans, but only the individual proteins Mre11p and Rad50p are widely and highly conserved; Xrs2p conservation is weak and its homologs are only present in eukaryotes (17, 18, 19 and reviewed in 20). In contrast to yeast mre11, rad50, and xrs2 null mutants, which are viable, loss of activity in any of the vertebrate homologs results in embryonic lethality or cell death (21, 22).
Mutations in the human homolog of MRE11 have been linked to the disease ataxia-telangiectasia-like disorder (OMIM), which is characterized by chromosomal instability, increased sensitivity to radiation, and progressive cerebellar degeneration (23 and references contained therein).
The nuclease activity of the MRX complex is mediated by the Mre11p subunit. Mre11p has both a 3'-5' exonuclease activity and a structurally specific endonuclease activity, which are manganese-dependent and localized to the N-terminus of the protein (24, 25). The N-terminal portion of Mre11p, which contains motifs shared by the phosphoesterase family, is also important for maintaining interaction with the other complex subunits, Xrs2p and Rad50p (12, 26). Xrs2p stimulates the exonuclease activity of Mre11p while Rad50p enhances the endonuclease activity (16, 25). The Mre11p C-terminus mediates DNA binding to both single- and double-stranded DNA in a structure- and sequence-specific manner (27, 12, 24).
Last updated: 2006-02-27