The MRN complex in double-strand break repair and telomere maintenance

Abstract

Genomes are subject to constant threat by damaging agents that generate DNA double-strand breaks (DSBs). The ends of linear chromosomes need to be protected from DNA damage recognition and end-joining, and this is achieved through protein-DNA complexes known as telomeres. The Mre11-Rad50-Nbs1 (MRN) complex plays important roles in detection and signaling of DSBs, as well as the repair pathways of homologous recombination (HR) and non-homologous end-joining (NHEJ). In addition, MRN associates with telomeres and contributes to their maintenance. Here, we provide an overview of MRN functions at DSBs, and examine its roles in telomere maintenance and dysfunction.

Fig. 1. Characteristics of the MRN complex

(A) Domain organization of Mre11, Rad50, and Nbs1. (B) Model of intermolecular interactions within the MRN·DNA ternary complex. While there is evidence that multiple MRN complexes can cluster at DNA termini, for simplicity only a single complex is depicted. See text for details. (C) Clustering of MRN complexes at DNA termini, and the subsequent tethering of multiple DNA molecules via the coiled-coil arms of Rad50. The DNA-binding globular heads of the MRN complexes are depicted by spheres.

Fig. 1. Characteristics of the MRN complex

(A) Domain organization of Mre11, Rad50, and Nbs1. (B) Model of intermolecular interactions within the MRN·DNA ternary complex. While there is evidence that multiple MRN complexes can cluster at DNA termini, for simplicity only a single complex is depicted. See text for details. (C) Clustering of MRN complexes at DNA termini, and the subsequent tethering of multiple DNA molecules via the coiled-coil arms of Rad50. The DNA-binding globular heads of the MRN complexes are depicted by spheres.

Fig. 2. Models of NHEJ

(A) C-NHEJ, also known as direct end joining, is carried out with minimal processing of the DSB termini prior to ligation. Both blunt and protruding termini are amenable to C-NHEJ. A single DSB can be processed via multiple routes, with the product sequence being determined by the chronology in which ligase, nuclease, and polymerase activities are employed. Blue regions denote gaps filled in by a DNA polymerase. (B) A-NHEJ involves modest resection of DSB ends (<100 nucleotides) until regions of microhomology are encountered which can guide reattachment of the DNA ends. Regions of microhomology are depicted in green.

Fig. 3. Human telomere structure

Specific interactions between shelterin components, and between these proteins and specific regions of telomeric DNA are highlighted. Looping back the 3′ G-overhang enables it to invade distal, duplex regions of the telomere and base pair with the complementary C-rich strand, giving rise to the t-loop structure. See text for details.