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Xu J, Zhao L, Peng S, et al. Mechanisms of distinctive mismatch tolerance between Rad51 and Dmc1 in homologous recombination. Nucleic Acids Res. 2021;49(22):13135-13149doi: 10.1093/nar/gkab1141.
Xu, J., Zhao, L., Peng, S., Chu, H., Liang, R., Tian, M., Connell, P. P., Li, G., Chen, C., & Wang, H. W. (2021). Mechanisms of distinctive mismatch tolerance between Rad51 and Dmc1 in homologous recombination. Nucleic acids research, 49(22), 13135-13149. https://doi.org/10.1093/nar/gkab1141
Xu, Jingfei, et al. "Mechanisms of distinctive mismatch tolerance between Rad51 and Dmc1 in homologous recombination." Nucleic acids research vol. 49,22 (2021): 13135-13149. doi: https://doi.org/10.1093/nar/gkab1141
Xu J, Zhao L, Peng S, Chu H, Liang R, Tian M, Connell PP, Li G, Chen C, Wang HW. Mechanisms of distinctive mismatch tolerance between Rad51 and Dmc1 in homologous recombination. Nucleic Acids Res. 2021 Dec 16;49(22):13135-13149. doi: 10.1093/nar/gkab1141. PMID: 34871438.
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Nucleic Acids Res. 2021 Dec 16;49(22):13135-13149. doi: 10.1093/nar/gkab1141.

Mechanisms of distinctive mismatch tolerance between Rad51 and Dmc1 in homologous recombination.

Nucleic acids research

Jingfei Xu, Lingyun Zhao, Sijia Peng, Huiying Chu, Rui Liang, Meng Tian, Philip P Connell, Guohui Li, Chunlai Chen, Hong-Wei Wang

Affiliations

  1. Ministry of Education Key Laboratory of Protein Sciences, Tsinghua-Peking Joint Center for Life Sciences, Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing, 100084, China.
  2. School of Life Sciences, Beijing Normal University, Beijing, 100875, China.
  3. Imaging and Characterization Core Lab, King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia.
  4. Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing, 100084, China.
  5. Laboratory of Molecular Modeling and Design, State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Science, 457 Zhongshan Road, Dalian, 116023, China.
  6. Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL 60615, USA.

PMID: 34871438 DOI: 10.1093/nar/gkab1141

Abstract

Homologous recombination (HR) is a primary DNA double-strand breaks (DSBs) repair mechanism. The recombinases Rad51 and Dmc1 are highly conserved in the RecA family; Rad51 is mainly responsible for DNA repair in somatic cells during mitosis while Dmc1 only works during meiosis in germ cells. This spatiotemporal difference is probably due to their distinctive mismatch tolerance during HR: Rad51 does not permit HR in the presence of mismatches, whereas Dmc1 can tolerate certain mismatches. Here, the cryo-EM structures of Rad51-DNA and Dmc1-DNA complexes revealed that the major conformational differences between these two proteins are located in their Loop2 regions, which contain invading single-stranded DNA (ssDNA) binding residues and double-stranded DNA (dsDNA) complementary strand binding residues, stabilizing ssDNA and dsDNA in presynaptic and postsynaptic complexes, respectively. By combining molecular dynamic simulation and single-molecule FRET assays, we identified that V273 and D274 in the Loop2 region of human RAD51 (hRAD51), corresponding to P274 and G275 of human DMC1 (hDMC1), are the key residues regulating mismatch tolerance during strand exchange in HR. This HR accuracy control mechanism provides mechanistic insights into the specific roles of Rad51 and Dmc1 in DNA double-strand break repair and may shed light on the regulatory mechanism of genetic recombination in mitosis and meiosis.

© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.

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