Regulation of RAD51 at the Transcriptional and Functional Levels: What Prospects for Cancer Therapy?
Abstract
:Simple Summary
Abstract
1. Introduction
2. Regulation of RAD51 Expression
2.1. Transcriptional Control of RAD51
2.1.1. Cyclin Dependent Kinases
2.1.2. Member of the E2F Transcription Factor Family
2.1.3. Other Transcription Factors
2.2. Chromatin-Mediated Regulation of RAD51 Gene Expression
3. Post-Translational Regulation of RAD51
3.1. Post-Translational Modifications Leading to Activation of RAD51
3.2. Post-Translational Modifications Leading to RAD51 Inactivation
3.3. RAD51 Loading and Stability at DSB Site by Protein–Protein Interactions
4. Pharmacological Inhibition of RAD51
5. Discussion
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
ATM | Ataxia-Telangiectasia Mutated |
ATR | Ataxia Telangiectasia and Rad3 Related |
BD | Bromodomain |
BET | Bromodomains and Extraterminal |
BRCA1 | Breast Cancer 1 |
BRCT | BRCA1 Carboxy-Terminus |
CCNK | Cyclin K |
CDK | Cyclin-Dependent Kinase |
ChIP | Chromatin Immunoprecipitation |
CHD4 | Chromodomain Helicase DNA-binding Protein 4 |
CK2 | Casein Kinase 2 |
CML | Chronic Myelogenous Leukemia |
CTD | C-Terminal Domain |
CtIP | CtBP-Interacting Protein |
DNA | Deoxyribonucleic acid (necessary?) |
DNA-PKcs | DNA-dependent Protein Kinase Catalytic Subunit |
DSB | Double-Strand Break |
ET | Extraterminal Domain |
GBM | Glioblastoma Multiforme |
H2AX | Histone 2AX |
HR | Homologous Recombination |
HRR | Homologous Recombination Repair |
H3K9Ac | Histone H3 at lysine 9 |
IR | Ionizing Radiation |
NHEJ | Non-Homologous End Joining |
PALB2 | Partner and Localizer of BRCA2 |
PARPi | Poly (ADP-ribose) Polymerase Inhibitors |
PLK1 | Polo-like kinase 1 |
RB | Retinoblastoma |
RPA | Replication Protein A |
SE | Super-Enhancers |
ssDNA | Single-Strand DNA |
TCGA | The Cancer Genome Atlas |
UV | Ultra-violet |
53BP1 | TP53-binding protein |
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Regulator of RAD51 | Function | Level of regulation | Effect on RAD51 | Drug Target |
---|---|---|---|---|
CDK12/CDK13 | RNA pol II regulator | mRNA expression | Activator | Yes |
E2F1 | Transcription Factor | mRNA expression | Activator | No |
E2F4 | Transcription Factor | mRNA expression | Repressor | No |
E2F7 | Transcription Factor | mRNA expression | Repressor | No |
FOXM1 | Transcription Factor | mRNA expression | Activator | No |
EGR1 | Transcription Factor | mRNA expression | Activator | No |
P53 | Transcription Factor | mRNA expression | Repressor | No |
BRD4 | Transcription Activator | mRNA expression | Activator | Yes |
CHD4 | Nucleosome Remodeler | mRNA expression | Activator | No |
PLK1 | Kinase | Post-translational | Activator | Yes |
CK2 | Kinase | Post-translational | Activator | Yes |
CHK1 | Kinase | Post-translational | Activator | Yes |
UCHL3 | Deubiquitinatinase | Post-translational | Activator | No |
FBH1 | Ubiquitin ligase | Post-translational | Repressor | No |
FBX05 | Ubiquitin ligase | Post-translational | Repressor | No |
RFWD3 | Ubiquitin ligase | Post-translational | Repressor | No |
RAD51C | RAD51 Cofactor | Homofilament Loading/stabilisation | Activator | No |
RAD51B | RAD51 Cofactor | Homofilament Loading | Activator | No |
RAD51D | RAD51 Cofactor | Homofilament Loading | Activator | No |
XRCC1 | RAD51 Cofactor | Homofilament stabilisation | Activator | No |
XRCC2 | RAD51 Cofactor | Homofilament Loading | Activator | No |
SWSAP1 | RAD51 Cofactor | Homofilament stabilisation | Activator | No |
PARI | DNA Helicase | Homofilament stabilisation | Repressor | No |
BLM | DNA Helicase | Homofilament stabilisation | Repressor | No |
Drug | Target | Trial phase | Trial Status | Results | Trial Number |
---|---|---|---|---|---|
CYT-0851 | RAD51 | Phase 1/2 | On going | Not reported | NCT03997968 |
Dinaciclib | Inhibition of multiple CDKs | Phase 1 | On going | Tolerable in combination with veliparib | NCT01434316 |
Anti-tumor activity is limited in non-BRCA carriers | |||||
INCB054329 | Inhibition of BET proteins | Phase 1/2 | Completed | 30% Stable disease | NCT02431260 |
43% Progressive disease | |||||
SYHA1801 | BRD4 | Phase 1 | On going | Not reported | NCT04309968 |
PLX51107 | BRD4 | Phase 1 | Completed | Tolerable except for patients with extensive hepatic metastasis | NCT04022785 |
Phase 1 | On going | Not reported | NCT04022785 | ||
BMS-986158 | Inhibition of BET proteins | Phase 1 | On going | Not reported | NCT03936465 |
AZD5153 | BRD4 | Phase 1 | Completed | Tolerable | NCT03205176 |
GSK525762 | Inhibition of BET proteins | Phase 1 | Completed | Manageable tolerability | NCT01587703 |
Volasertib | PLK1 | Phase 3 | Completed | Did not meet primary objectif in combination with cytarabine | NCT01721876 |
Onvansertib | PLK1 | Phase 2 | On going | Not reported | NCT03414034 |
TAK-960 | PLK1 | Phase 1 | Completed | Terminated due to lack of efficacy | NCT01179399 |
CYC140 | PLK1 | Phase 1 | Completed | Not reported | NCT03884829 |
NMS-1286937 | PLK1 | Phase 1 | Completed | Tolerable | NCT01014429 |
CX-4945 | CK2 | Phase 1/2 | Completed | Not reported | NCT02128282 |
Phase 1/2 | On going | Not reported | NCT03904862 | ||
MK-8776 | CHK1 | Phase 2 | Completed | Similar result as control arm | NCT01870596 |
SRA737 | CHK1 | Phase 1/2 | Completed | Tolerable | NCT02797964 |
Phase 1/2 | Completed | Tolerable | NCT02797977 | ||
LY2603618 | CHK1 | Phase 1/2 | Completed | Toxicy when combined with pemetrexed+Cisplatin | NCT01139775 |
Prexasertib | CHK1 | Phase 2 | On going | Tolerable, only modest activity in BRCA mutant HGSOC patients | NCT02203513 |
Phase 2 | On going | Not reported | NCT03414047 |
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Orhan, E.; Velazquez, C.; Tabet, I.; Sardet, C.; Theillet, C. Regulation of RAD51 at the Transcriptional and Functional Levels: What Prospects for Cancer Therapy? Cancers 2021, 13, 2930. https://doi.org/10.3390/cancers13122930
Orhan E, Velazquez C, Tabet I, Sardet C, Theillet C. Regulation of RAD51 at the Transcriptional and Functional Levels: What Prospects for Cancer Therapy? Cancers. 2021; 13(12):2930. https://doi.org/10.3390/cancers13122930
Chicago/Turabian StyleOrhan, Esin, Carolina Velazquez, Imene Tabet, Claude Sardet, and Charles Theillet. 2021. "Regulation of RAD51 at the Transcriptional and Functional Levels: What Prospects for Cancer Therapy?" Cancers 13, no. 12: 2930. https://doi.org/10.3390/cancers13122930