Regulation of RAD51 at the Transcriptional and Functional Levels: What Prospects for Cancer Therapy?
The RAD51 recombinase is a critical effector of Homologous Recombination (HR), which is an essential DNA repair mechanism for double-strand breaks. The RAD51 protein is recruited onto the DNA break by BRCA2 and forms homopolymeric filaments that invade the homologous chromatid and use it as a templa...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-06-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/13/12/2930 |
| _version_ | 1797530465574322176 |
|---|---|
| author | Esin Orhan Carolina Velazquez Imene Tabet Claude Sardet Charles Theillet |
| author_facet | Esin Orhan Carolina Velazquez Imene Tabet Claude Sardet Charles Theillet |
| author_sort | Esin Orhan |
| collection | DOAJ |
| description | The RAD51 recombinase is a critical effector of Homologous Recombination (HR), which is an essential DNA repair mechanism for double-strand breaks. The RAD51 protein is recruited onto the DNA break by BRCA2 and forms homopolymeric filaments that invade the homologous chromatid and use it as a template for repair. RAD51 filaments are detectable by immunofluorescence as distinct foci in the cell nucleus, and their presence is a read out of HR proficiency. RAD51 is an essential gene, protecting cells from genetic instability. Its expression is low and tightly regulated in normal cells and, contrastingly, elevated in a large fraction of cancers, where its level of expression and activity have been linked with sensitivity to genotoxic treatment. In particular, BRCA-deficient tumors show reduced or obliterated RAD51 foci formation and increased sensitivity to platinum salt or PARP inhibitors. However, resistance to treatment sets in rapidly and is frequently based on a complete or partial restoration of RAD51 foci formation. Consequently, RAD51 could be a highly valuable therapeutic target. Here, we review the multiple levels of regulation that impact the transcription of the RAD51 gene, as well as the post-translational modifications that determine its expression level, recruitment on DNA damage sites and the efficient formation of homofilaments. Some of these regulation levels may be targeted and their impact on cancer cell survival discussed. |
| first_indexed | 2024-03-10T10:29:22Z |
| format | Article |
| id | doaj.art-81fb9579a1d8417da148477004a54053 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T10:29:22Z |
| publishDate | 2021-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-81fb9579a1d8417da148477004a540532023-11-21T23:45:30ZengMDPI AGCancers2072-66942021-06-011312293010.3390/cancers13122930Regulation of RAD51 at the Transcriptional and Functional Levels: What Prospects for Cancer Therapy?Esin Orhan0Carolina Velazquez1Imene Tabet2Claude Sardet3Charles Theillet4IRCM, Institut de Recherche en Cancérologie de Montpellier U1194 INSERM, Université de Montpellier, 34090 Montpellier, FranceICM, Institut du Cancer de Montpellier, 34090 Montpellier, FranceIRCM, Institut de Recherche en Cancérologie de Montpellier U1194 INSERM, Université de Montpellier, 34090 Montpellier, FranceIRCM, Institut de Recherche en Cancérologie de Montpellier U1194 INSERM, Université de Montpellier, 34090 Montpellier, FranceIRCM, Institut de Recherche en Cancérologie de Montpellier U1194 INSERM, Université de Montpellier, 34090 Montpellier, FranceThe RAD51 recombinase is a critical effector of Homologous Recombination (HR), which is an essential DNA repair mechanism for double-strand breaks. The RAD51 protein is recruited onto the DNA break by BRCA2 and forms homopolymeric filaments that invade the homologous chromatid and use it as a template for repair. RAD51 filaments are detectable by immunofluorescence as distinct foci in the cell nucleus, and their presence is a read out of HR proficiency. RAD51 is an essential gene, protecting cells from genetic instability. Its expression is low and tightly regulated in normal cells and, contrastingly, elevated in a large fraction of cancers, where its level of expression and activity have been linked with sensitivity to genotoxic treatment. In particular, BRCA-deficient tumors show reduced or obliterated RAD51 foci formation and increased sensitivity to platinum salt or PARP inhibitors. However, resistance to treatment sets in rapidly and is frequently based on a complete or partial restoration of RAD51 foci formation. Consequently, RAD51 could be a highly valuable therapeutic target. Here, we review the multiple levels of regulation that impact the transcription of the RAD51 gene, as well as the post-translational modifications that determine its expression level, recruitment on DNA damage sites and the efficient formation of homofilaments. Some of these regulation levels may be targeted and their impact on cancer cell survival discussed.https://www.mdpi.com/2072-6694/13/12/2930RAD51homologous recombinationDNA repairgenomic instabilityDNA breakcancer therapy |
| spellingShingle | Esin Orhan Carolina Velazquez Imene Tabet Claude Sardet Charles Theillet Regulation of RAD51 at the Transcriptional and Functional Levels: What Prospects for Cancer Therapy? Cancers RAD51 homologous recombination DNA repair genomic instability DNA break cancer therapy |
| title | Regulation of RAD51 at the Transcriptional and Functional Levels: What Prospects for Cancer Therapy? |
| title_full | Regulation of RAD51 at the Transcriptional and Functional Levels: What Prospects for Cancer Therapy? |
| title_fullStr | Regulation of RAD51 at the Transcriptional and Functional Levels: What Prospects for Cancer Therapy? |
| title_full_unstemmed | Regulation of RAD51 at the Transcriptional and Functional Levels: What Prospects for Cancer Therapy? |
| title_short | Regulation of RAD51 at the Transcriptional and Functional Levels: What Prospects for Cancer Therapy? |
| title_sort | regulation of rad51 at the transcriptional and functional levels what prospects for cancer therapy |
| topic | RAD51 homologous recombination DNA repair genomic instability DNA break cancer therapy |
| url | https://www.mdpi.com/2072-6694/13/12/2930 |
| work_keys_str_mv | AT esinorhan regulationofrad51atthetranscriptionalandfunctionallevelswhatprospectsforcancertherapy AT carolinavelazquez regulationofrad51atthetranscriptionalandfunctionallevelswhatprospectsforcancertherapy AT imenetabet regulationofrad51atthetranscriptionalandfunctionallevelswhatprospectsforcancertherapy AT claudesardet regulationofrad51atthetranscriptionalandfunctionallevelswhatprospectsforcancertherapy AT charlestheillet regulationofrad51atthetranscriptionalandfunctionallevelswhatprospectsforcancertherapy |