Exploring the Origin and Physiological Significance of DNA Double Strand Breaks in the Developing Neuroretina
Abstract
:1. Introduction
2. DSBs and Neural Development
3. DSBs and Early Neural Cell Death
4. Mechanisms Underlying Specific DSBs: A Potential role for RAG-1,2 in Neural Development?
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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NHEJ MUTATED GENE (and Function) | MURINE NEURAL PHENOTYPE | HUMAN PHENOTYPE Immune System and Genomic Stability | HUMAN PHENOTYPE Nervous System |
---|---|---|---|
LIG IV (DSB sealing) | Lethal in E14-E16 (depending on the study). Increased apoptosis in early postmitotic neurons. Acellularity in central and peripheral nervous system [15,37,38]. | Immunodeficiency (residual T and B cells), pancytopenia, lymphomas, leukemia [36]. | (Only hypomorphic mutants described). Microcephaly (non progressive after birth). Delayed development, primordial dwarfism and neurological abnormalities. Dubowitz syndrome, LIG4 syndrome [39]. |
Nhej-1/XLF/Cernunnos (DSB sealing) | Viable. Frequent spontaneous genomic instability, including translocations [40]. Increased neuronal cell death and neuronal migration defects in brain cortex [15,41]. | Immunodeficiency (residual T and B cells), neutropenia, macrocytic anemia, autoimmunity [42,43]. | In hypomorphic mutants, microcephaly, delayed development, chromosomal translocations. Nijmegen breakage syndrome-like phenotype, polymicrogyria [39]. |
XRCC4 (DSB sealing) | Lethal in E14,5. Increased apoptosis in early postmitotic neurons, acellularity in central and peripheral nervous system [15]. | Genomic instability, hypersensitivity to radiation and cancer predisposition [44]. | Microcephaly and delayed development. [44] Primordial dwarfism [45]. |
Pol β (DSB gap filling)) | Neonatal lethality. Increased apoptosis in early postmitotic neurons, apoptosis in central and peripheral nervous system, genomic instability [15]. | Genomic instability [46]. | Reduced activity in patients with Alzheimer disease [47]. |
DNA-PK (Nuclease. DSB end processing) | Viable. Increased apoptosis in early retina postmitotic neurons [48]. Altered axonal emission [49]. If combined with Pol β deficiency, lethal in E11,5, delayed embryonic development and massive neuronal apoptosis [15,50]. | Severe combined immunodeficiency, total loss of T and B cells [51,52]. | Microcephaly, delayed development, progressive neural degeneration and telomere shrinkage [39,53]. |
Artemis (Nuclease. DSB end processing) | Viable. Hypersensitivity to radiation and genomic instability, including telomeric fusions [54]. | Progressive immunodeficiency, reaching total T and B cell loss, autoimmunity and Omenn Syndrome. Leukemia and non lymphoid carcinomas [39]. | Not described. |
MRE11/NBS1-1/RAD50 (Sensor of DNA damage) | Lethal at E6. Elevated genomic instability [55,56]. | Predisposition to lymphomas, breast and ovary cancer [39]. | Nijmegen breakage syndrome (NBS), microcephaly and ataxia [39]. |
KU 70/80 (Recognition of DNA lesions) | Viable. Increased apoptosis in early postmitotic neurons, especially in the retina [57]. | Suspected to induce embryonic lethality due to telomeric instability [58]. | Melanoma brain metastases with high genomic instability [59]. |
ATM (Sensor of DNA damage) | Viable. Delayed embryonic development, with neurologic disfunction [15]. Specific loss of a subpopulation of dopaminergic neurons [60]. Hypersensitivity to radiation. [61]. | Reduced or absent levels of IgE, IgA and IgG2, genomic instability, telomere shrinkage and lymphoma predisposition [39]. | Ataxia, progressive neurodegeneration, ocular telangiectasia [39]. |
Polymerase mu (DSB gap filling) | Viable. Increased apoptosis in early retina postmitotic neurons, ectopic neurons and axonal pathfinding cues, and altered axonal emission [62]. Increased learning and brain long term potentiation in aged mice [63]. | Not described in humans, but altered hematopoiesis has been detected in mice [64]. | Not described. |
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Álvarez-Lindo, N.; Suárez, T.; de la Rosa, E.J. Exploring the Origin and Physiological Significance of DNA Double Strand Breaks in the Developing Neuroretina. Int. J. Mol. Sci. 2022, 23, 6449. https://doi.org/10.3390/ijms23126449
Álvarez-Lindo N, Suárez T, de la Rosa EJ. Exploring the Origin and Physiological Significance of DNA Double Strand Breaks in the Developing Neuroretina. International Journal of Molecular Sciences. 2022; 23(12):6449. https://doi.org/10.3390/ijms23126449
Chicago/Turabian StyleÁlvarez-Lindo, Noemí, Teresa Suárez, and Enrique J. de la Rosa. 2022. "Exploring the Origin and Physiological Significance of DNA Double Strand Breaks in the Developing Neuroretina" International Journal of Molecular Sciences 23, no. 12: 6449. https://doi.org/10.3390/ijms23126449
APA StyleÁlvarez-Lindo, N., Suárez, T., & de la Rosa, E. J. (2022). Exploring the Origin and Physiological Significance of DNA Double Strand Breaks in the Developing Neuroretina. International Journal of Molecular Sciences, 23(12), 6449. https://doi.org/10.3390/ijms23126449