Mechanisms of Programmed DNA Lesions and Genomic Instability in the Immune System

Alt, Frederick W.; Zhang, Yu; Meng, Fei-Long; Guo, Chunguang; Schwer, Bjoern

doi:10.1016/j.cell.2013.01.007

Cited by 429 publications

(654 citation statements)

References 103 publications

(263 reference statements)

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“…51,52 It is also an essential process in the development of the immune response with the purpose of generating enormous antibody diversity of Ig and T-cell receptor genes, thus enabling defense against a wide variety of specific pathogens. 4 Consequently, deficiencies in NHEJ proteins lead to RS-SCID or RS-CID because DSBs are left unrepaired, misrepaired, or repaired with a substantial delay. DSBs are the most significant DNA lesions; unrepaired DSBs can cause cell death, and misrepaired DSBs cause genomic instability and lead to mutations.…”

Section: Discussionmentioning

confidence: 99%

“…3 Approximately 30% of SCID patients have defects in V(D)J recombination (antigen receptor recombination), an essential process for the normal development of T and B lymphocytes. 4 This process randomly combines variable (V), diverse (D), and joining (J) gene segments in lymphocytes. 5 V(D)J defects lead to T-and Bcell lymphocytopenia and a classic T-B-natural killer þ SCID phenotype.…”

mentioning

confidence: 99%

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Evaluation of Severe Combined Immunodeficiency and Combined Immunodeficiency Pediatric Patients on the Basis of Cellular Radiosensitivity

Lobachevsky

Woodbine

Hsiao

et al. 2015

The Journal of Molecular Diagnostics

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Pediatric patients with severe or nonsevere combined immunodeficiency have increased susceptibility to severe, life-threatening infections and, without hematopoietic stem cell transplantation, may fail to thrive. A subset of these patients have the radiosensitive (RS) phenotype, which may necessitate conditioning before hematopoietic stem cell transplantation, and this conditioning includes radiomimetic drugs, which may significantly affect treatment response. To provide statistical criteria for classifying cellular response to ionizing radiation as the measure of functional RS screening, we analyzed the repair capacity and survival of ex vivo irradiated primary skin fibroblasts from five dysmorphic and/or developmentally delayed pediatric patients with severe combined immunodeficiency and combined immunodeficiency. We developed a mathematical framework for the analysis of g histone 2A isoform X foci kinetics to quantitate DNA-repair capacity, thus establishing crucial criteria for identifying RS. The results, presented in a diagram showing each patient as a point in a 2D RS map, were in agreement with findings from the assessment of cellular RS by clonogenic survival and from the genetic analysis of factors involved in the nonhomologous end-joining repair pathway. We provide recommendations for incorporating into clinical practice the functional assays and genetic analysis used for establishing RS status before conditioning. This knowledge would enable the selection of the most appropriate treatment regimen, reducing the risk for severe therapy-related adverse effects. Severe combined immunodeficiency (SCID) and combined immunodeficiency (CID) are rare genetic disorders. The incidence of SCID in Australia is 1 in 69,000 live births, 1 comparable to the reported incidence of 1 in 100,000 births worldwide. CID patients have increased susceptibility to invasive and opportunistic bacterial, viral, and fungal infections due to poor T-lymphocyte production and/or function, in addition to failure of B lymphocytes to generate functional antibodies. SCID is the extreme form of CID. Patients with this condition often present in the first year of life, with severe life-threatening infections, and consequently failure to thrive, requiring prompt intervention. SCID without treatment is usually fatal within the first year of life. 2 Both SCID and CID are genetically diverse syndromes, and over 50 molecular defects resulting in these syndromes have been described. 3 Approximately 30% of SCID patients have defects in V(D)J recombination (antigen receptor

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Evaluation of Severe Combined Immunodeficiency and Combined Immunodeficiency Pediatric Patients on the Basis of Cellular Radiosensitivity

Lobachevsky

Woodbine

Hsiao

et al. 2015

The Journal of Molecular Diagnostics

View full text Add to dashboard Cite

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“…During B cell development, events such as V(D)J recombination, CSR, and SHM lead to chromatin remodeling and DNA damage that make the B cells susceptible to transformation. Defects in the response to DNA damage and genomic instability have been shown to result in immunodeficiency disorders (54). Thus, misregulation of the genes involved in the DNA damage response may be an important reason why resting B cells are impaired in the absence of PRMT7.…”

Section: Discussionmentioning

confidence: 99%

Histone Arginine Methylation by PRMT7 Controls Germinal Center Formation via Regulating Bcl6 Transcription

Ying

Mei

Zhang

et al. 2015

The Journal of Immunology

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B cells are the center of humoral immunity and produce Abs to protect against foreign Ags. B cell defects lead to diseases such as leukemia and lymphomas. Histone arginine methylation is important for regulating gene activation and silencing in cells. Although the process commonly exists in mammalian cells, its roles in B cells are unknown. To explore the effects of aberrant histone arginine methylation on B cells, we generated mice with a B cell–specific knockout of PRMT7, a member of the methyltransferases that mediate arginine methylation of histones. In this article, we showed that the loss of PRMT7 led to decreased mature marginal zone B cells and increased follicular B cells and promoted germinal center formation after immunization. Furthermore, mice lacking PRMT7 expression in B cells secreted low levels of IgG1 and IgA. Abnormal expression of germinal center genes (i.e., Bcl6, Prdm1, and Irf4) was detected in conditional knockout mice. By overexpressing PRMT7 in the Raji and A20 cell lines derived from B cell lymphomas, we validated the fact that PRMT7 negatively regulated Bcl6 expression. Using chromatin immunoprecipitation–PCR, we found that PRMT7 could recruit H4R3me1 and symmetric H4R3me2 to the Bcl6 promoter. These results provide evidence for the important roles played by PRMT7 in germinal center formation.

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“…In germ line cells, the components of the immunoglobulin and T cell receptor genes are sequentially arranged as distinct arrays of variable (V), diversity (D) or joining (J) segments [36]. During immune development, the gene segments undergo rearrangement via the process of V(D)J recombination to produce distinct re-arrangements of V, D and J sub-fragments.…”

Section: The Exploitation Of Nhej During the Development Of The Immunmentioning

confidence: 99%

“…During immune development, the gene segments undergo rearrangement via the process of V(D)J recombination to produce distinct re-arrangements of V, D and J sub-fragments. The process of V(D)J recombination has, like NHEJ, been described in several excellent reviews and only an outline will be given here [36][37][38]. In germ line cells, each V, D or J segment has a coding region, C, and a flanking recombination signal sequence (RSS).…”

Section: The Exploitation Of Nhej During the Development Of The Immunmentioning

confidence: 99%

Reprint of “The clinical impact of deficiency in DNA non-homologous end-joining”

2014

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Double strand break repair V(D)J recombination (Severe) combined immunodeficiency -(S)CID Human syndromes a b s t r a c t DNA non-homologous end-joining (NHEJ) is the major DNA double strand break (DSB) repair pathway in mammalian cells. Defects in NHEJ proteins confer marked radiosensitivity in cell lines and mice models, since radiation potently induces DSBs. The process of V(D)J recombination functions during the development of the immune response, and involves the introduction and rejoining of programmed DSBs to generate an array of diverse T and B cells. NHEJ rejoins these programmed DSBs. Consequently, NHEJ deficiency confers (severe) combined immunodeficiency -(S)CID -due to a failure to carry out V(D)J recombination efficiently. NHEJ also functions in class switch recombination, another step enhancing T and B cell diversity. Prompted by these findings, a search for radiosensitivity amongst (S)CID patients revealed a radiosensitive sub-class, defined as RS-SCID. Mutations in NHEJ genes, defining human syndromes deficient in DNA ligase IV (LIG4 Syndrome), XLF-Cernunnos, Artemis or DNA-PKcs, have been identified in such patients. Mutations in XRCC4 or Ku70,80 in patients have not been identified. RS-SCID patients frequently display additional characteristics including microcephaly, dysmorphic facial features and growth delay. Here, we overview the clinical spectrum of RS-SCID patients and discuss our current understanding of the underlying biology.

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Mechanisms of Programmed DNA Lesions and Genomic Instability in the Immune System

Cited by 429 publications

References 103 publications

Evaluation of Severe Combined Immunodeficiency and Combined Immunodeficiency Pediatric Patients on the Basis of Cellular Radiosensitivity

Evaluation of Severe Combined Immunodeficiency and Combined Immunodeficiency Pediatric Patients on the Basis of Cellular Radiosensitivity

Histone Arginine Methylation by PRMT7 Controls Germinal Center Formation via Regulating Bcl6 Transcription

Reprint of “The clinical impact of deficiency in DNA non-homologous end-joining”

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