9q9i
From Proteopedia
Cryo-EM structure of human Mre11-Rad50-Nbs1 complex bound to DNA
Structural highlights
DiseaseNBN_HUMAN Nijmegen breakage syndrome;Hereditary breast and ovarian cancer syndrome;Familial prostate cancer. The disease is caused by mutations affecting the gene represented in this entry. Disease susceptibility is associated with variations affecting the gene represented in this entry. Disease susceptibility may be associated with variations affecting the gene represented in this entry. Defects in NBN might play a role in the pathogenesis of childhood acute lymphoblastic leukemia (ALL).[1] FunctionNBN_HUMAN Component of the MRE11-RAD50-NBN (MRN complex) which plays a critical role in the cellular response to DNA damage and the maintenance of chromosome integrity. The complex is involved in double-strand break (DSB) repair, DNA recombination, maintenance of telomere integrity, cell cycle checkpoint control and meiosis. The complex possesses single-strand endonuclease activity and double-strand-specific 3'-5' exonuclease activity, which are provided by MRE11. RAD50 may be required to bind DNA ends and hold them in close proximity. NBN modulate the DNA damage signal sensing by recruiting PI3/PI4-kinase family members ATM, ATR, and probably DNA-PKcs to the DNA damage sites and activating their functions. It can also recruit MRE11 and RAD50 to the proximity of DSBs by an interaction with the histone H2AX. NBN also functions in telomere length maintenance by generating the 3' overhang which serves as a primer for telomerase dependent telomere elongation. NBN is a major player in the control of intra-S-phase checkpoint and there is some evidence that NBN is involved in G1 and G2 checkpoints. The roles of NBS1/MRN encompass DNA damage sensor, signal transducer, and effector, which enable cells to maintain DNA integrity and genomic stability. Forms a complex with RBBP8 to link DNA double-strand break sensing to resection. Enhances AKT1 phosphorylation possibly by association with the mTORC2 complex.[2] [3] [4] [5] [6] Publication Abstract from PubMedThe MRE11-RAD50-NBS1 (MRN) complex is a central, multifunctional factor in the detection, signaling and nucleolytic processing of DNA double-strand breaks (DSBs). To clarify how human MRN binds generic and telomeric DNA ends and can separate DNA end sensing from nuclease activities, we determined cryo-electron microscopy (cryo-EM) structures of human MRN bound to DNA and to DNA and the telomere protection factor TRF2. MRN senses DSBs through a tight clamp-like sensing state with closed coiled-coil domains, but auto-inhibited MRE11 nuclease. NBS1 wraps around the MRE11 dimer, with NBS1's ATM recruitment motif sequestered by binding to the regulatory RAD50 S site, necessitating a switch in the NBS1 C helix for ATM activation. At telomeric DNA, TRF2 blocks the second S site via the iDDR motif to prevent nuclease and ATM activation. Our results provide a structural framework for DNA sensing via a gating mechanism and separation of sensing, signaling and processing activities of mammalian MRN. Structural basis for DNA break sensing by human MRE11-RAD50-NBS1 and its regulation by telomeric factor TRF2.,Fan Y, Kuybu F, Cui H, Lammens K, Chen JX, Kugler M, Jung C, Hopfner KP Nat Commun. 2025 Sep 18;16(1):8320. doi: 10.1038/s41467-025-64082-x. PMID:40968163[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Homo sapiens | Large Structures | Cui HJ | Fan YL | Hopfner KP | Kuybu F | Lammens K
