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Mechanisms of distinctive mismatch tolerance between Rad51 and Dmc1 in homologous recombination
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 sp...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8682777/ https://www.ncbi.nlm.nih.gov/pubmed/34871438 http://dx.doi.org/10.1093/nar/gkab1141 |
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author | Xu, Jingfei Zhao, Lingyun Peng, Sijia Chu, Huiying Liang, Rui Tian, Meng Connell, Philip P Li, Guohui Chen, Chunlai Wang, Hong-Wei |
author_facet | Xu, Jingfei Zhao, Lingyun Peng, Sijia Chu, Huiying Liang, Rui Tian, Meng Connell, Philip P Li, Guohui Chen, Chunlai Wang, Hong-Wei |
author_sort | Xu, Jingfei |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8682777 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-86827772021-12-20 Mechanisms of distinctive mismatch tolerance between Rad51 and Dmc1 in homologous recombination Xu, Jingfei Zhao, Lingyun Peng, Sijia Chu, Huiying Liang, Rui Tian, Meng Connell, Philip P Li, Guohui Chen, Chunlai Wang, Hong-Wei Nucleic Acids Res Structural Biology 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. Oxford University Press 2021-12-06 /pmc/articles/PMC8682777/ /pubmed/34871438 http://dx.doi.org/10.1093/nar/gkab1141 Text en © The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Structural Biology Xu, Jingfei Zhao, Lingyun Peng, Sijia Chu, Huiying Liang, Rui Tian, Meng Connell, Philip P Li, Guohui Chen, Chunlai Wang, Hong-Wei Mechanisms of distinctive mismatch tolerance between Rad51 and Dmc1 in homologous recombination |
title | Mechanisms of distinctive mismatch tolerance between Rad51 and Dmc1 in homologous recombination |
title_full | Mechanisms of distinctive mismatch tolerance between Rad51 and Dmc1 in homologous recombination |
title_fullStr | Mechanisms of distinctive mismatch tolerance between Rad51 and Dmc1 in homologous recombination |
title_full_unstemmed | Mechanisms of distinctive mismatch tolerance between Rad51 and Dmc1 in homologous recombination |
title_short | Mechanisms of distinctive mismatch tolerance between Rad51 and Dmc1 in homologous recombination |
title_sort | mechanisms of distinctive mismatch tolerance between rad51 and dmc1 in homologous recombination |
topic | Structural Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8682777/ https://www.ncbi.nlm.nih.gov/pubmed/34871438 http://dx.doi.org/10.1093/nar/gkab1141 |
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