The Inherited Basis of Human Radiosensitivity

Gatti, Richard A.

doi:10.1080/02841860152619115

Cited by 159 publications

(96 citation statements)

References 85 publications

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“…Perhaps the closest phenotype to that of hSNM1B knockdown cells occurs in cells derived from patients with FA, particularly in terms of their sensitivity to ICL-inducing agents in survival and chromosome stability. There are also several reports of increased radiosensitivity in FA cells (Carreau et al, 1999;Garcia-Higuera et al, 2001;Gatti, 2001;Digweed et al, 2002). Given this similarity, we considered the possibility that hSNM1B might function in the FA/ BRCA pathway.…”

Section: Discussionmentioning

confidence: 88%

“…Cells derived from FA patients are characterized by chromosomal instability and hypersensitivity to ICL-inducing agents and, in at least some cases, to ionizing radiation (IR) (Carreau et al, 1999;Garcia-Higuera et al, 2001;Gatti, 2001;Digweed et al, 2002). The disease has a high degree of heterogeneity, with 11 known complementation groups (FA-A, B, C, D1, D2, E, F, G, I, J and K) (Levitus et al, 2003) and eight genes (FANCA, C, D1/BRCA2, D2, E, F, G, L) cloned thus far (Strathdee et al, 1992;Lo Len Foe et al, 1996; The Fanconi anaemia/breast cancer Consortium, 1996;de Winter et al, 1998de Winter et al, , 2000aTimmers et al, 2001;Howlett et al, 2002;Meetei et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

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Human SNM1B is required for normal cellular response to both DNA interstrand crosslink-inducing agents and ionizing radiation

2004

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DNA interstrand crosslinks (ICLs) are critical lesions for the mammalian cell since they affect both DNA strands and block transcription and replication. The repair of ICLs in the mammalian cell involves components of different repair pathways such as nucleotide-excision repair and the double-strand break/homologous recombination repair pathways. However, the mechanistic details of mammalian ICL repair have not been fully delineated. We describe here the complete coding sequence and the genomic organization of hSNM1B, one of at least three human homologs of the Saccharomyces cerevisiae PSO2 gene. Depletion of hSNM1B by RNA interference rendered cells hypersensitive to ICL-inducing agents. This requirement for hSNM1B in the cellular response to ICL has been hypothesized before but never experimentally verified. In addition, siRNA knockdown of hSNM1B rendered cells sensitive to ionizing radiation, suggesting the possibility of hSNM1B involvement in homologous recombination repair of double-strand breaks arising as intermediates of ICL repair. Monoubiquitination of FANCD2, a key step in the FANC/BRCA pathway, is not affected in hSNM1B-depleted HeLa cells, indicating that hSNM1B is probably not a part of the Fanconi anemia core complex. Nonetheless, similarities in the phenotype of hSNM1B-depleted cells and cultured cells from patients suffering from Fanconi anemia make hSNM1B a candidate for one of the as yet unidentified Fanconi anemia genes not involved in monoubiquitination of FANCD2.

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Section: Discussionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Human SNM1B is required for normal cellular response to both DNA interstrand crosslink-inducing agents and ionizing radiation

2004

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“…Ionizing radiation induces both DNA singlestrand breaks and double-strand breaks (DSB), with the DSBs generally considered the lethal event (2). Several syndromes associated with increased radiosensitivity are caused by deficiencies in genes of DSB repair, leading to the hypothesis that the individual repair capacity for these lesions should be an important determinant of individual radiosensitivity (3,4). Here, three polymorphisms in genes involved in homologous recombination (XRCC3 Thr 241 Met, XRCC2 Arg 188 His, and NBS1 Glu 185 Gln) with potential functional effects (5-8) were evaluated for a possible association with the risk of developing acute skin reactions following radiotherapy in a prospective epidemiologic study.…”

Section: Introductionmentioning

confidence: 99%

Genetic Polymorphisms in the DNA Double-Strand Break Repair Genes XRCC3, XRCC2, and NBS1 Are Not Associated with Acute Side Effects of Radiotherapy in Breast Cancer Patients

Popanda

Tan

Ambrosone

et al. 2006

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…Main clinical features include progressive cerebellar 51 degeneration leading to severe neuromotor dysfunction, oculocutaneous telangiectasia, profound 52 immunodeficiency of both humoral and cellular compartments, gonadal dysgenesis, growth 53 retardation in some patients, predisposition to malignancies (primarily lymphoreticular), high levels 54 of serum alpha-fetoprotein, and acute radiosensitivity. A-T cells show chromosomal instability, 55 premature senescence, accelerated telomere shortening, sensitivity to the cytotoxic and clastogenic 56 effects of ionizing radiation and radiomimetic chemicals, and defective activation of cell-cycle 57 checkpoints by these agents (Boder and Sedgwick, 1970;Gatti, 2001;Shiloh, 2006). The A-T 58 mutated gene (ATM) encodes for a serine/threonine protein kinase recruited and activated by DNA 59 double-strand breaks.…”

Section: Introduction 49mentioning

confidence: 99%

Blood metal levels and related antioxidant enzyme activities in patients with ataxia telangiectasia

Squadrone

Brizio

Mancini

et al. 2015

Neurobiology of Disease

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23Transition metals are co-factors for a wide range of vital enzymes, and are directly or indirectly 24 involved in the response against reactive oxygen species (ROS), which can damage cellular 25 components. Their altered homeostasis has been studied in neurodegenerative disorders such as 26Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic Lateral Sclerosis (ALS), but 27 no data are available on rarer conditions. 28We aimed at studying the role of essential trace elements in Ataxia-Telengiectasia (A-T), a rare 29 form of paediatric autosomal recessive cerebellar ataxia with altered antioxidant response. We 30 found an increased level of copper (Cu, p=0.0002), and a reduced level of zinc (Zn, p=0.0002) in 31 the blood of patients (n. 16) compared to controls, using inductively coupled plasma mass 32 spectrometry (ICP-MS). Other trace elements involved in the oxidative stress response, such as 33 manganese (Mn) and selenium (Se) were unaltered. Cu/Zn-dependent superoxide dismutase 34 (SOD1) was shown to have a 30% reduction in gene expression and 40% reduction in enzyme 35 activity upon analysis of lymphoblastoid cell lines of patients (Student's t-test, p=0.0075). We also 36 found a 30% reduction of Mn-SOD (SOD2; Student's t-test, p=0.02), probably due to a feedback 37 regulatory loop between the two enzymes. The expression of antioxidant enzymes, such as 38 erythrocyte glutathione peroxidase (GPX1), and SOD2 was unaltered, whereas catalase (CAT) was 39 increased in A-T cells, both at the mRNA level and in terms of enzyme activity (~25%). Enhanced 40 CAT expression can be attributed to the high ROS status, which induces CAT transcription. 41

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The Inherited Basis of Human Radiosensitivity

Cited by 159 publications

References 85 publications

Human SNM1B is required for normal cellular response to both DNA interstrand crosslink-inducing agents and ionizing radiation

Human SNM1B is required for normal cellular response to both DNA interstrand crosslink-inducing agents and ionizing radiation

Genetic Polymorphisms in the DNA Double-Strand Break Repair Genes XRCC3, XRCC2, and NBS1 Are Not Associated with Acute Side Effects of Radiotherapy in Breast Cancer Patients

Blood metal levels and related antioxidant enzyme activities in patients with ataxia telangiectasia

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