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Structure paper

TitleStructural Basis for Polθ-Helicase DNA Binding and Microhomology-Mediated End-Joining.
Journal, issue, pagesbioRxiv, Year 2024
Publish dateJun 7, 2024
AuthorsFumiaki Ito / Ziyuan Li / Leonid Minakhin / Htet A Khant / Richard T Pomerantz / Xiaojiang S Chen /
PubMed AbstractDNA double-strand breaks (DSBs) present a critical threat to genomic integrity, often precipitating genomic instability and oncogenesis. Repair of DSBs predominantly occurs through homologous ...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 (Polθ) becomes critical for DSB repair via microhomology-mediated end joining (MMEJ), also termed theta-mediated end joining (TMEJ). Thus, Polθ 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 Polθ-mediated MMEJ remain poorly understood. Here we present a series of cryo-electron microscopy structures of the Polθ helicase domain (Polθ-hel) in complex with DNA containing 3'-overhang. The structures reveal the sequential conformations adopted by Polθ-hel during the critical phases of DNA binding, microhomology searching, and microhomology annealing. The stepwise conformational changes within the Polθ-hel subdomains and its functional dimeric state are pivotal for aligning the 3'-overhangs, facilitating the microhomology search and subsequent annealing necessary for DSB repair via MMEJ. Our findings illustrate the essential molecular switches within Polθ-hel that orchestrate the MMEJ process in DSB repair, laying the groundwork for the development of targeted therapies against the Polθ-hel.
External linksbioRxiv / PubMed:38895274 / PubMed Central
MethodsEM (single particle)
Resolution3.1 - 3.8 Å
Structure data

43706

8w0a

EMDB-43706, PDB-8w0a:
Human DNA polymerase theta helicase domain in complex with ssDNA, dimer form
Method: EM (single particle) / Resolution: 3.2 Å

43816

9asj

EMDB-43816, PDB-9asj:
Human DNA polymerase theta helicase domain in complex with AMP-PNP, dimer form
Method: EM (single particle) / Resolution: 3.5 Å

43817

9ask

EMDB-43817, PDB-9ask:
Human DNA polymerase theta helicase domain dimer, apo-form
Method: EM (single particle) / Resolution: 3.6 Å

43818

9asl

EMDB-43818, PDB-9asl:
Human DNA polymerase theta helicase domain tetramer, apo-form
Method: EM (single particle) / Resolution: 3.5 Å

EMDB-45217: Human DNA polymerase theta helicase domain in microhomology annealed state 1, dimer form
Method: EM (single particle) / Resolution: 3.8 Å

45218

9c5q

EMDB-45218, PDB-9c5q:
Human DNA polymerase theta helicase domain in microhomology annealed state 2, dimer form
Method: EM (single particle) / Resolution: 3.1 Å

Chemicals

ChemComp-ANP:
PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / AMP-PNP, energy-carrying molecule analogue*YM

Source
  • homo sapiens (human)
KeywordsTRANSFERASE/DNA / DNA repair / helicase / ATPase / TRANSFERASE-DNA complex / TRANSFERASE / DNA BINDING PROTEIN

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