9asl | pdb_00009asl

Human DNA polymerase theta helicase domain tetramer, apo-form

spinqualitylabelsall models 9asl, resolution 3.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9asl is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.5Å Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function DPOLQ_HUMAN Has a DNA polymerase activity on nicked double-stranded DNA and on a singly primed DNA template. The enzyme activity is resistant to aphidicolin, and inhibited by dideoxynucleotides. Exhibites a single-stranded DNA-dependent ATPase activity. Could be involved in the repair of interstrand cross-links. Publication Abstract from PubMed DNA double-strand breaks (DSBs) present a critical threat to genomic integrity, often precipitating genomic instability and oncogenesis. Repair of DSBs predominantly occurs through homologous recombination (HR) and non-homologous end joining (NHEJ). In HR-deficient cells, DNA polymerase theta (Poltheta) becomes critical for DSB repair via microhomology-mediated end joining (MMEJ), also termed theta-mediated end joining (TMEJ). Thus, Poltheta is synthetically lethal with BRCA1/2 and other HR factors, underscoring its potential as a therapeutic target in HR-deficient cancers. However, the molecular mechanisms governing Poltheta-mediated MMEJ remain poorly understood. Here we present a series of cryo-electron microscopy structures of the Poltheta helicase domain (Poltheta-hel) in complex with DNA containing different 3'-ssDNA overhangs. The structures reveal the sequential conformations adopted by Poltheta-hel during the critical phases of DNA binding, microhomology searching, and microhomology annealing. The stepwise conformational changes within the Poltheta-hel subdomains and its functional dimeric state are pivotal for aligning the 3'-ssDNA overhangs, facilitating the microhomology search and subsequent annealing necessary for DSB repair via MMEJ. Our findings illustrate the essential molecular switches within Poltheta-hel that orchestrate the MMEJ process in DSB repair, laying the groundwork for the development of targeted therapies against the Poltheta-hel. Structural basis for Poltheta-helicase DNA binding and microhomology-mediated end-joining.,Ito F, Li Z, Minakhin L, Khant HA, Pomerantz RT, Chen XS Nat Commun. 2025 Apr 19;16(1):3725. doi: 10.1038/s41467-025-58441-x. PMID:40253368 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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