Identified in a genetic screen for mutants that are sensitive to ionizing radiation (4) RAD50 is a member of the RAD52 epistasis group. Other members of this group include RAD51, RAD52, RAD54, RDH54, RAD55, RAD57, RAD59, MRE11, 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 2 and 5).

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 (6, 7). Complex functions include DNA binding, exonuclease and endonuclease activities, DNA unwinding, and DNA end recognition (8, 9, 10). 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 2 and 5).

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 (11, 12, 13 and reviewed in 14). 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 (15, 16).

The Rad50p subunit belongs to the family of structural maintenance of chromosome (SMC) proteins (17). Like other proteins in this family, it has two globular ATPase domains at its N- and C-terminal ends separated by a long coiled-coil region made up of heptad repeats (17, 6, 18). The ATPase domains of Rad50p mediate the ATP-dependent activities of DNA binding and unwinding (19, 9). Additionally, the ATPase domains facilitate protein-protein interaction and stimulation of Mre11p nuclease activity (9, 20). Within the coiled-coil region is a conserved zinc-binding motif known as the ''RAD50 hook'' which is thought to mediate interaction between the coiled-coil region of two Rad50p molecules (18). The structural characteristics of Rad50p in addition to mutational studies of the complex suggest that one of the functions of MRX is to bridge gaps between DNA molecules and bring the ends of DSBs together (18, 21, and reviewed in 5).

Last updated: 2006-02-27