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Update on DNA-Double Strand Break Repair Defects in Combined Primary Immunodeficiency
Mary A Slatter1,2, Andrew R Gennery3,4
1Paediatric Immunology and Haematopoietic Stem Cell Transplantation, Great North Children's Hospital, Clinical Resource Building, Floor 4, Block 2, Newcastle upon Tyne, UK.
Purpose Of Review:
The most serious DNA damage, DNA double strand breaks (DNA-dsb), leads to mutagenesis, carcinogenesis or apoptosis if left unrepaired. Non-homologous end joining (NHEJ) is the principle repair pathway employed by mammalian cells to repair DNA-dsb. Several proteins are involved in this pathway, defects in which can lead to human disease. This review updates on the most recent information available for the specific diseases associated with the pathway.
Recent Findings:
A new member of the NHEJ pathway, PAXX, has been identified, although no human disease has been associated with it. The clinical phenotypes of Artemis, DNA ligase 4, Cernunnos-XLF and DNA-PKcs deficiency have been extended. The role of haematopoietic stem cell transplantation, following reduced intensity conditioning chemotherapy, for many of these diseases is being advanced. In the era of newborn screening, urgent genetic diagnosis is necessary to correctly target appropriate treatment for patients with DNA-dsb repair disorders.
Insights
DNA double-strand breaks (DNA-dsb) are critical damage repaired by non-homologous end joining (NHEJ). This review details diseases linked to NHEJ pathway defects and advances in treating these conditions.
Area of Science:
- Molecular Biology
- Genetics
- Cellular Biology
Background:
- DNA double-strand breaks (DNA-dsb) represent severe genetic damage.
- Unrepaired DNA-dsb can result in mutagenesis, cancer, or cell death.
- Non-homologous end joining (NHEJ) is the primary mammalian DNA-dsb repair pathway.
Observation:
- The NHEJ pathway involves multiple proteins, and defects can cause human diseases.
- A novel NHEJ component, PAXX, has been identified, but its disease association is unknown.
- Clinical data for Artemis, DNA ligase 4, Cernunnos-XLF, and DNA-PKcs deficiencies have been expanded.
Findings:
- The clinical phenotypes associated with deficiencies in key NHEJ proteins have been further elucidated.
- The therapeutic potential of reduced-intensity conditioning chemotherapy followed by hematopoietic stem cell transplantation is being explored for these disorders.
- Recent advancements highlight the necessity of rapid genetic diagnosis for effective treatment of DNA-dsb repair disorders.
Implications:
- Understanding NHEJ pathway variations is crucial for diagnosing and managing genetic disorders.
- New therapeutic strategies, including stem cell transplantation, offer hope for patients with DNA-dsb repair defects.
- Early genetic diagnosis is vital for timely and appropriate intervention in newborns with DNA-dsb repair disorders.
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