Mechanisms of distinctive mismatch tolerance between Rad51 and Dmc1 in homologous recombination
© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research..
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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2021 |
|---|---|
| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:49 |
|---|---|
| Enthalten in: |
Nucleic acids research - 49(2021), 22 vom: 16. Dez., Seite 13135-13149 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Xu, Jingfei [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
9007-49-2 |
|---|
| Anmerkungen: |
Date Completed 10.01.2022 Date Revised 04.04.2024 published: Print Citation Status MEDLINE |
|---|
| doi: |
10.1093/nar/gkab1141 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM334081513 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM334081513 | ||
| 003 | DE-627 | ||
| 005 | 20240404233419.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2021 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1093/nar/gkab1141 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1364.xml |
| 035 | |a (DE-627)NLM334081513 | ||
| 035 | |a (NLM)34871438 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Xu, Jingfei |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Mechanisms of distinctive mismatch tolerance between Rad51 and Dmc1 in homologous recombination |
| 264 | 1 | |c 2021 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 10.01.2022 | ||
| 500 | |a Date Revised 04.04.2024 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Cell Cycle Proteins |2 NLM | |
| 650 | 7 | |a DNA-Binding Proteins |2 NLM | |
| 650 | 7 | |a Multiprotein Complexes |2 NLM | |
| 650 | 7 | |a DNA |2 NLM | |
| 650 | 7 | |a 9007-49-2 |2 NLM | |
| 650 | 7 | |a Rad51 Recombinase |2 NLM | |
| 650 | 7 | |a EC 2.7.7.- |2 NLM | |
| 650 | 7 | |a DMC1 protein, human |2 NLM | |
| 650 | 7 | |a EC 3.6.1.- |2 NLM | |
| 700 | 1 | |a Zhao, Lingyun |e verfasserin |4 aut | |
| 700 | 1 | |a Peng, Sijia |e verfasserin |4 aut | |
| 700 | 1 | |a Chu, Huiying |e verfasserin |4 aut | |
| 700 | 1 | |a Liang, Rui |e verfasserin |4 aut | |
| 700 | 1 | |a Tian, Meng |e verfasserin |4 aut | |
| 700 | 1 | |a Connell, Philip P |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Guohui |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Chunlai |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Hong-Wei |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Nucleic acids research |d 1974 |g 49(2021), 22 vom: 16. Dez., Seite 13135-13149 |w (DE-627)NLM000063398 |x 1362-4962 |7 nnns |
| 773 | 1 | 8 | |g volume:49 |g year:2021 |g number:22 |g day:16 |g month:12 |g pages:13135-13149 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1093/nar/gkab1141 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 49 |j 2021 |e 22 |b 16 |c 12 |h 13135-13149 | ||