9bi4
cryo EM structure of dsDNA bound Mre11-Rad50 complex
Structural highlights
FunctionRAD50_YEAST Component of the MRN complex, which plays a central role in double-strand break (DSB) repair, DNA recombination, maintenance of telomere integrity and meiosis (PubMed:26896444, PubMed:28134932). The MRN complex is involved in the repair of DNA double-strand breaks (DSBs) via homologous recombination (HR), an error-free mechanism which primarily occurs during S and G2 phases (By similarity). The complex (1) mediates the end resection of damaged DNA, which generates proper single-stranded DNA, a key initial steps in HR, and is (2) required for the recruitment of other repair factors and efficient activation of TEL1/ATM and ATR upon DNA damage (PubMed:26896444, PubMed:28134932). The MRN complex possesses single-strand endonuclease activity and double-strand-specific 3'-5' exonuclease activity, which are provided by MRE11, to initiate end resection, which is required for single-strand invasion and recombination (By similarity). Within the complex, RAD50 is both required to bind DNA ends and hold them in close proximity and regulate the activity of MRE11 (PubMed:26896444). RAD50 provides an ATP-dependent control of MRE11 by positioning DNA ends into the MRE11 active site: ATP-binding induces a large structural change from an open form with accessible MRE11 nuclease sites into a closed form (By similarity). The MRN complex is also required for the processing of R-loops (PubMed:31537797).[UniProtKB:Q92878][UniProtKB:Q9X1X1][1] [2] [3] Publication Abstract from PubMedThe Mre11 complex comprises Mre11, Rad50 and Nbs1 (Xrs2 in S. cerevisiae). The core components, Mre11 and Rad50 are highly conserved, with readily identifiable orthologs in all clades of life, whereas Nbs1/Xrs2 are present only in eukaryotes. In eukaryotes, the complex is integral to the DNA damage response, acting in DNA double strand break (DSB) detection and repair, and the activation of DNA damage signaling. We present here a 3.2 A cryo-EM structure of the S. cerevisiae Mre11-Rad50 complex with bound dsDNA. The structure provided a foundation for detailed mutational analyses regarding homo and heterotypic protein interfaces, as well as DNA binding properties of Rad50. We define several conserved residues in Rad50 and Mre11 that are critical to complex assembly as well as for DNA binding. In addition, the data reveal that the Rad50 coiled coil domain influences ATP hydrolysis over long distances. Structure guided functional analysis of the S. cerevisiae Mre11 complex.,Petrini J, Hohl M, Yu Y, Kuryavyi V, Patel D Res Sq [Preprint]. 2024 Dec 9:rs.3.rs-5390974. doi: 10.21203/rs.3.rs-5390974/v1. PMID:39711558[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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