XCIND as a genetic disease of X-irradiation hypersensitivity and cancer susceptibility

Mizutani, Shuki; Takagi, Motoki

doi:10.1007/s12185-012-1240-5

Cited by 14 publications

(14 citation statements)

References 26 publications

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“…More than twenty molecules are involved in the V(D) J recombination and CSR; and inability to persecute the programmed DDR results in primary immunodeficiency (PID) ( Table 1) [3,6,[8][9][10][11][12][13][14][15]. The patients with defect either in DNA damage signal or in NHEJ process present PID phenotype, and often show one or more of phenotypes that include radiosensitivity, predisposition to malignancy, developmental delay, and neurological deficits ( Table 2).…”

Section: Dna Damage Repair Networkmentioning

confidence: 99%

Recent advances in the study of immunodeficiency and DNA damage response

Morio

2017

Int J Hematol

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DNA breaks can be induced by exogenous stimuli or by endogenous stress, but are also generated during recombination of V, D, and J genes (V(D)J recombination), immunoglobulin class switch recombination (CSR). Among various DNA breaks generated, DNA double strand break (DSB) is the most deleterious one. DNA damage response (DDR) is initiated when DSBs are detected, leading to DNA break repair by non-homologous end joining (NHEJ). The process is critically important for the generation of diversity for foreign antigens; and failure to exert DNA repair leads to immunodeficiency such as severe combined immunodeficiency and hyper-IgM syndrome. In V(D)J recombination, DSBs are induced by RAG1/2; and generated post-cleavage hairpins are resolved by Artemis/DNA-PKcs/KU70/KU80. DDR is initiated by ataxia-telangiectasia mutated as a master regulator together with MRE11/RAD50/NBS1 complex. Finally, DSBs are repaired by NHEJ. The defect of one of the molecules shows various degree of immunodeficiency and radiosensitivity. Upon CSR inducing signal, DSBs induced by activation-induced cytidine deaminase and endonucleases elicit DDR. Broken ends are repaired either by NHEJ or by mismatch repair system. Patients with radiosensitive SCID require hematopoietic cell transplantation as a curative therapy; but the procedures for eradication of recipient hematopoietic cells are often associated with severe toxicity.

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Section: Dna Damage Repair Networkmentioning

confidence: 99%

Recent advances in the study of immunodeficiency and DNA damage response

Morio

2017

Int J Hematol

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“…Inability to persecute the programmed DDR and repair results in the developmental disorder in T, B cells, that is, primary immunodeficiency (PID). These PID patients often show one or more of phenotypes that include radiosensitivity, predisposition to malignancy, developmental delay, or neurological deficits such as microcephaly, which has been called XCIND [1]. These disorders provide us with an insight into physiological importance and function of each molecule in health and disease.…”

Section: Dr T Morio Focused On Primary Immunodeficiency (Pid) V(d)mentioning

confidence: 99%

DNA damage response and disorders with hematology, oncology and immunology

Mizutani

2017

Int J Hematol

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“…Ataxia-telangiectasia (A-T [MIM 607585]) is a rare autosomal-recessive disorder characterised by hyper-radiosensitivity, cancer predisposition, immunodeficiency and neurodegeneration 9 . A-T is caused by germline mutations in the ataxia-telangiectasia mutated ( ATM ) gene encoding ATM kinase, which is a DSB damage response master kinase member of the evolutionarily conserved phosphatidylinositol-3-kinase-related kinase (PIKK) family 10 .…”

Section: Introductionmentioning

confidence: 99%

“…Previous epidemiological studies demonstrated that A-T heterozygous carriers showed a several-fold increased risk of breast and ovarian cancers in comparison with normal individuals 11 . Since A-T heterozygous carriers, who are clinically asymptomatic, exist at a rate of approximately 1% in human populations 9 , we assume that the heterozygous form of recessive mutations associated with hyper-radiosensitive genetic disorders such as A-T when in a homozygous state might be a genetic determinant of individual differences in healthy human populations. Previous studies indicated that most primary cells from A-T heterozygous carriers were more radiosensitive than those from normal individuals 12 , while it was also reported that the radiosensitivities of A-T heterozygous carriers and normal individuals were not segregated because of the genetic heterogeneity in some cases 13 .…”

Section: Introductionmentioning

confidence: 99%

Evaluation of ATM heterozygous mutations underlying individual differences in radiosensitivity using genome editing in human cultured cells

Royba

Miyamoto

Akutsu

et al. 2017

Sci Rep

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Ionizing radiation (IR) induces DNA double-strand breaks (DSBs), which are an initial step towards chromosomal aberrations and cell death. It has been suggested that there are individual differences in radiosensitivity within human populations, and that the variations in DNA repair genes might determine this heterogeneity. However, it is difficult to quantify the effect of genetic variants on the individual differences in radiosensitivity, since confounding factors such as smoking and the diverse genetic backgrounds within human populations affect radiosensitivity. To precisely quantify the effect of a genetic variation on radiosensitivity, we here used the CRISPR-ObLiGaRe (Obligate Ligation-Gated Recombination) method combined with the CRISPR/Cas9 system and a nonhomologous end joining (NHEJ)-mediated knock-in technique in human cultured cells with a uniform genetic background. We generated ATM heterozygous knock-out (ATM +/−) cell clones as a carrier model of a radiation-hypersensitive autosomal-recessive disorder, ataxia-telangiectasia (A-T). Cytokinesis-blocked micronucleus assay and chromosome aberration assay showed that the radiosensitivity of ATM +/− cell clones was significantly higher than that of ATM +/+ cells, suggesting that ATM gene variants are indeed involved in determining individual radiosensitivity. Importantly, the differences in radiosensitivity among the same genotype clones were small, unlike the individual differences in fibroblasts derived from A-T-affected family members.

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XCIND as a genetic disease of X-irradiation hypersensitivity and cancer susceptibility

Cited by 14 publications

References 26 publications

Recent advances in the study of immunodeficiency and DNA damage response

Recent advances in the study of immunodeficiency and DNA damage response

DNA damage response and disorders with hematology, oncology and immunology

Evaluation of ATM heterozygous mutations underlying individual differences in radiosensitivity using genome editing in human cultured cells

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