Update on DNA-Double Strand Break Repair Defects in Combined Primary Immunodeficiency

Slatter, Mary; Gennery, Andrew R.

doi:10.1007/s11882-020-00955-z

Cited by 18 publications

(17 citation statements)

References 99 publications

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“…The radiosensitive status of any patient undergoing such treatments should be evaluated as to avoid these pejorative outcomes. Likewise, any patient undergoing HSCT should be evaluated for a possible DNA repair defect and the conditioning regimen attenuated accordingly as to avoid catastrophic outcome following transplantation (83).…”

Section: Discussionmentioning

confidence: 99%

Inborn Errors of Immunity caused by defects of the DNA damage response pathways

Fournier

Mahlaoui

Moshous

et al. 2022

Preprint

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Several inborn errors of immunity are caused by defects in the general DNA repair machinery as exemplified by the T-B- RS-SCID condition owing to impaired resolution of programmed DNA double strands breaks introduced by RAG1/2 during V(D)J recombination. The genome instability generally associated with these conditions results in an increased propensity to develop malignancies requiring genotoxic based anti-cancer treatments. Moreover, the extent of immune deficiency often calls for hematopoietic stem cell transplantation as a definitive treatment, thus also demanding genotoxic based conditioning regimen prior to transplantation. In both cases, the underlying general DNA repair defects may result in catastrophic iatrogenic consequences. It is therefore of paramount importance to assess the functionality of the DNA repair apparatus prior to any genotoxic treatment when the exact molecular cause of the disease is unknown. For this purpose, two simple assays can be used on patient’s derived peripheral blood lymphocytes. 1) The PROMIDISα biomarker, based on the next generation sequencing analysis of the TCRα will highlight specific signatures of DNA repair deficiencies. 2) Direct analysis of the sensitivity of peripheral lymphocytes to ionizing radiations will formally identify patients at risk to develop toxicity towards genotoxic based treatments.

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Section: Discussionmentioning

confidence: 99%

Inborn Errors of Immunity caused by defects of the DNA damage response pathways

Fournier

Mahlaoui

Moshous

et al. 2022

Preprint

View full text Add to dashboard Cite

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“…Although we did not study apoptotic response, impaired survival to IR has been reported for B lymphocytes and resting T cells. Interestingly, particularly B lymphocytes and naïve T cells are diminished in patients with DNA repair deficiencies ( 16 , 46 , 47 ).…”

Section: Discussionmentioning

confidence: 99%

“…Genetic defects in ATM lead to ataxia telangiectasia (AT) presenting with combined immunodeficiency, genomic instability with predisposition to cancer, severe cellular sensitivity to IR, and cerebellar degeneration ( 15 ). Individuals affected by inborn DNA repair defects, including AT, often present with lymphopenia, predominantly reduced naïve T cells and B cells, and hypogammaglobinemia ( 16 ). In order to provide adequate treatment to these patients and to minimize DNA damaging diagnostic and treatment procedures, early diagnosis and classification of these diseases is highly important to affected individuals.…”

Section: Introductionmentioning

confidence: 99%

Differential DNA Damage Response of Peripheral Blood Lymphocyte Populations

et al. 2021

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DNA damage occurs constantly in every cell triggered by endogenous processes of replication and metabolism, and external influences such as ionizing radiation and intercalating chemicals. Large sets of proteins are involved in sensing, stabilizing and repairing this damage including control of cell cycle and proliferation. Some of these factors are phosphorylated upon activation and can be used as biomarkers of DNA damage response (DDR) by flow and mass cytometry. Differential survival rates of lymphocyte subsets in response to DNA damage are well established, characterizing NK cells as most resistant and B cells as most sensitive to DNA damage. We investigated DDR to low dose gamma radiation (2Gy) in peripheral blood lymphocytes of 26 healthy donors and 3 patients with ataxia telangiectasia (AT) using mass cytometry. γH2AX, p-CHK2, p-ATM and p53 were analyzed as specific DDR biomarkers for functional readouts of DNA repair efficiency in combination with cell cycle and T, B and NK cell populations characterized by 20 surface markers. We identified significant differences in DDR among lymphocyte populations in healthy individuals. Whereas CD56+CD16+ NK cells showed a strong γH2AX response to low dose ionizing radiation, a reduced response rate could be observed in CD19+CD20+ B cells that was associated with reduced survival. Interestingly, γH2AX induction level correlated inversely with ATM-dependent p-CHK2 and p53 responses. Differential DDR could be further noticed in naïve compared to memory T and B cell subsets, characterized by reduced γH2AX, but increased p53 induction in naïve T cells. In contrast, DDR was abrogated in all lymphocyte populations of AT patients. Our results demonstrate differential DDR capacities in lymphocyte subsets that depend on maturation and correlate inversely with DNA damage-related survival. Importantly, DDR analysis of peripheral blood cells for diagnostic purposes should be stratified to lymphocyte subsets.

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“…Two pathways are important to resolve the damage and maintain genome stability following DNA-dsb: homologous recombination and non-homologous end-joining (NHEJ) ( 3 , 4 ). The first one requires an extensive sequence homology between the broken DNA and a donor DNA molecule and entails a templated DNA synthesis as a key step in the repair process.…”

Section: Introductionmentioning

confidence: 99%

Case Report: Wide Spectrum of Manifestations of Ligase IV Deficiency: Report of 3 Cases

et al. 2022

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DNA ligase IV deficiency is a rare autosomal recessive disorder associated with impaired DNA repair mechanisms. Most patients with DNA repair defects present with neurologic deficits, combined immunodeficiency, bone marrow failure, and/or hematologic neoplasia. We present 3 unrelated cases of ligase IV deficiency with different clinical presentations. Patient 1 presented at the age of 5 with bone marrow failure, dysmorphic features, and T and B lymphopenia. A compound heterozygous variant L19W/K635fs in the LIG4 gene was identified. Patient 2 presented at the age of 16 with recurrent infections. He had agammaglobulinemia and absent B cells. A homozygous R278H in the LIG4 gene was identified. Patient 3 was referred for vitiligo and B-cell lymphopenia (low class-switched B cells) and hypogammaglobulinemia. Homozygous R278H in LIG4 was also identified. In the last few years, the spectrum of clinical manifestations caused by ligase IV deficiency has widened, making it very difficult to establish an accurate clinical diagnosis. The use of NGS allows a proper diagnosis and provides a better prognosis and adequate family counseling.

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Update on DNA-Double Strand Break Repair Defects in Combined Primary Immunodeficiency

Cited by 18 publications

References 99 publications

Inborn Errors of Immunity caused by defects of the DNA damage response pathways

Inborn Errors of Immunity caused by defects of the DNA damage response pathways

Differential DNA Damage Response of Peripheral Blood Lymphocyte Populations

Case Report: Wide Spectrum of Manifestations of Ligase IV Deficiency: Report of 3 Cases

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