Canonical and Noncanonical Roles of Fanconi Anemia Proteins: Implications in Cancer Predisposition
Abstract
:Simple Summary
Abstract
1. Introduction
2. Canonical Role of FA Proteins: FA Signaling in the DNA ICL Repair Pathway
3. Noncanonical Role of FA Proteins
3.1. Expanded Nuclear Functions of FA Proteins outside ICLs Removal
3.1.1. FA and Replication Stress
3.1.2. FA in DSB Repair
3.1.3. FA and Transcription‒Replication Conflicts
3.2. Emerging Cytosolic Roles of FA Proteins
3.2.1. Mitochondria
3.2.2. Endocrinopathies
3.2.3. Inflammation
3.2.4. Virophagy
4. Hematopoietic Defects in FA Patients
5. FA Proteins and Cancer Predisposition
5.1. DNA Damage Response-Targeted Therapies in FA Patients
5.2. Clinical Implications for Emerging FA Noncanonical Roles in Cancer Predisposition
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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FA Gene | Alternative Name and Location | Key Features | Canonical Role | Cytosolic Noncanonical Role | Cancer Type Predisposition | |
---|---|---|---|---|---|---|
FANCA | - | 16q24.3 | Fanconi anemia core complex | Promotes FANCD2/I heterodimer monoubiquitylation | Interact with cytochrome P450 to respond oxidative damage; mitophagy effector | - |
FANCB | - | Xp22.2 | Fanconi anemia core complex | Promotes FANCD2/I heterodimer monoubiquitylation | - | - |
FANCC | - | 9q22.32 | Fanconi anemia core complex | Promotes FANCD2/I heterodimer monoubiquitylation | Interact with cytochrome P450 to respond oxidative damage; mitophagy effector through PARKIN interaction; virophagy mediator | Breast cancer |
FANCD1 | BRCA2 | 13q12. 3 | RAD51 activator | Fork stabilization; homologous recombination | Involved in mitophagy | AML; T-ALL; ALL; brain tumor; medulloblastoma; squamous cell carcinoma; breast cancer |
FANCD2 | - | 3p25.3 | FANCI binding partner | Monoubiquitylated by the core complex; promote the unhooking | Regulation of mitochondrial nucleoid complex components Atad3 and Tufm; sustain stem cells functions through SF3Bq spliceosomal protein interaction; Involved in mitophagy | - |
FANCE | - | 6p21.31 | Fanconi anemia core complex | Promotes FANCD2/I heterodimer monoubiquitylation | - | - |
FANCF | - | 11p14.3 | Fanconi anemia core complex | Promotes FANCD2/I heterodimer monoubiquitylation | Involved in mitophagy; virophagy mediator | - |
FANCG | - | 9p13.3 | Fanconi anemia core complex | Promotes FANCD2/I heterodimer monoubiquitylation | Interact with cytochrome P450 to respond oxidative damage; involved in mitochondria morphology regulation | - |
FANCI | - | 15q26.1 | FANCD2 binding partner | Several functions in the ICL repair | Sustain stem cells functions through SF3Bq spliceosomal protein interaction | - |
FANCJ | BRIP1 | 17q23.2 | BRCA1-interacting protein helicase | Promotes HR through BRCA1 binding | DNA-dependent ATPase activity | Ovarian cancer |
FANCL | - | 2p16.1 | E3 ubiquitin ligase of the Fanconi anemia core complex | Promotes FANCD2/I heterodimer monoubiquitylation | β-Catenin ubiquitination; involved in mitophagy; virophagy mediator | - |
FANCM | - | 14q21. 2 | ATR-activated DNA helicase | Recruits the FA core complex | - | Breast cancer |
FANCN | PALB2 | 16p12.2 | Partner and localizer of BRCA2 | Promotes HR and RAD51 activity | - | AML; medulloblastoma; neuroblastoma; Wilms Tumor; breast cancer |
FANCO | RAD51C | 17q23 | RAD51 paralog | HR | - | Ovarian cancer |
FANCP | SLX4 | 16p13.3 | Multidomain scaffold protein | Nuclease scaffold for ICL unhooking | - | |
FANCQ | ERCC4 | 16p13.12 | DNA repair endonuclease | DNA incision for ICL unhooking | - | |
FANCR | RAD51 | 15q15.1 | DNA recombinase | Fork stabilization and HR | Regulation of axonal branching through Netrin-1 modulation | |
FANCS | BRCA1 | 17q21.31 | E3 ubiquitin ligase | CMG complex unloading; Homologous recombination | Involved in mitophagy | Breast, ovarian cancer and leukemia |
FANCT | UBE2T | 1q32.1 | E2 ubiquitin ligase of the Fanconi anemia core complex | Promotes FANCD2/I heterodimer monoubiquitylation | - | |
FANCU | XRCC2 | 7q36.1 | DNA repair protein | HR | - | |
FANCV | REV7 | 1p36.22 | DNA polymerase | Translesion DNA synthesis | - | |
FANCW | - | 16q23.1 | E3 ubiquitin ligase | Essential for RAD51 turnover | - |
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Milletti, G.; Strocchio, L.; Pagliara, D.; Girardi, K.; Carta, R.; Mastronuzzi, A.; Locatelli, F.; Nazio, F. Canonical and Noncanonical Roles of Fanconi Anemia Proteins: Implications in Cancer Predisposition. Cancers 2020, 12, 2684. https://doi.org/10.3390/cancers12092684
Milletti G, Strocchio L, Pagliara D, Girardi K, Carta R, Mastronuzzi A, Locatelli F, Nazio F. Canonical and Noncanonical Roles of Fanconi Anemia Proteins: Implications in Cancer Predisposition. Cancers. 2020; 12(9):2684. https://doi.org/10.3390/cancers12092684
Chicago/Turabian StyleMilletti, Giacomo, Luisa Strocchio, Daria Pagliara, Katia Girardi, Roberto Carta, Angela Mastronuzzi, Franco Locatelli, and Francesca Nazio. 2020. "Canonical and Noncanonical Roles of Fanconi Anemia Proteins: Implications in Cancer Predisposition" Cancers 12, no. 9: 2684. https://doi.org/10.3390/cancers12092684