Assessing ‘radiosensitivity’ with kinetic profiles of γ-H2AX, 53BP1 and BRCA1 foci

Martin, Nathan; Nahas, Shareef; Tunuguntla, Rashmi; Fike, Francesca; Gatti, Richard A.

doi:10.1016/j.radonc.2011.05.065

Cited by 30 publications

(30 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Colony survival assay and radioresistant DNA synthesis have been validated for clinical diagnostic testing and colony survival assay was reported to be one of the most reliable assays to identify A-T patients [19].…”

Section: Germ Line Mutation Of Dna Damage Response-associated Gene Inmentioning

confidence: 99%

DNA damage response and hematological malignancy

Takagi

2017

Int J Hematol

View full text Add to dashboard Cite

errors. The metabolites, reactive oxygen species, reactive nitrogen species, reactive carbonyl species, lipid peroxidation products affect DNA integrity. Other than these metabolites, V(D)J recombination process mediated by RAG1/2 during lymphocyte development involves DNA double-strand breaks (DSB). DNA topoisomerase 2 also induces DSB to control DNA topologic status. Deamination induced by deaminases or depurination leads to DNA single-strand breaks (SSB). SSBs can also arise by DNA topoisomerase 1. Tens of thousands of SSBs, 10-50 DSBs per cell per day occur naturally [1][2][3]. ATM is a key regulator of DNA damage check pointOnce cells suffer DNA damage, cells try to resolve damages. The cellular response to DNA damage induces cell cycle arrest, damaged DNA repair, or apoptosis. This machinery is called DNA damage response (DDR), or DNA damage checkpoint. Numerous factors are involved in this process. The central player in DNA damage response, especially in DSB, is ATM. DNA damage response comprised several steps, sensor, transducer, and effector. When DNA DSB happen, the sensor, MRE11-RAD50-NBN (MRN) complex, is recruited to the DSB site [4]. ATM is present as a dimer or higher order multimer in unstressed cell with the kinase domain bound to a region surrounding Ser 1981 that is contained within the FAT domain. Cellular irradiation induces rapid intermolecular autophosphorylation of serine-1981 and this phosphorylation event results in dimer dissociation and initiation of cellular ATM kinase activity [5]. Then activated ATM recruited DSB site. Activated ATM transduces the signal to downstream effectors by phosphorylating Abstract DNA damage is a serious threat to cellular homeostasis. Damaged DNA leads to genomic instability, mutation, senescence, and/or cell death. DNA damage triggers a cellular response called the DNA damage response (DDR), followed by activation of the DNA repair machinery. DDR both maintains cellular homeostasis and prevents cancer development. Germ line mutation of DDRassociated genes can lead to cancer-susceptible syndromes. Somatic mutation of DDR-associated genes has also been reported in various tumors, including hematological malignancies. Therapeutic approaches that target the DDR and DNA repair are thus now being developed. Understanding the mechanism(s) underlying DDR and DNA repair will increase our knowledge of cancer etiology and facilitate development of cancer therapies.

show abstract

Section: Germ Line Mutation Of Dna Damage Response-associated Gene Inmentioning

confidence: 99%

DNA damage response and hematological malignancy

Takagi

2017

Int J Hematol

View full text Add to dashboard Cite

show abstract

“…Gamma irradiation (IR) is known to cause doublestranded DNA breaks, and these breaks and their subsequent repair can be monitored by the presence of gamma-H2AX, a phosphorylated histone variant involved in DNA repair 30 . WTNPCs showed very few gamma-H2AX foci-positive cells (X4 foci per nucleus) 24 h after IR, indicating that DNA repair had been successfully completed by that time point 31 (Fig. 3d).…”

Section: Physiological Phenotypes Of At Cells In Vitromentioning

confidence: 95%

“…The gamma-H2AX and ATM-pS1981 foci staining have been previously described 29,31,47 . Briefly, cells on coverslips were irradiated with 2 Gy using a Mark IV Cs-137 gamma irradiation source (dose rate B4.5 Gy min À 1 ).…”

Section: Methodsmentioning

confidence: 99%

SMRT compounds abrogate cellular phenotypes of ataxia telangiectasia in neural derivatives of patient-specific hiPSCs

et al. 2013

Self Cite

View full text Add to dashboard Cite

Ataxia telangiectasia is a devastating neurodegenerative disease caused primarily by loss of function mutations in ATM, a hierarchical DNA repair gene and tumour suppressor. So far, murine models of ataxia telangiectasia have failed to accurately recapitulate many aspects of the disease, most notably, the progressive cerebellar ataxia. Here we present a model of human ataxia telangiectasia using induced pluripotent stem cells, and show that small molecule read-through compounds, designed to induce read-through of mRNA around premature termination codons, restore ATM activity and improve the response to DNA damage. This platform allows for efficient screening of novel compounds, identification of target and off-target effects, and preclinical testing on relevant cell types for the pathogenic dissection and treatment of ataxia telangiectasia.

show abstract

“…Radiosensitivity is the most traditional and reliable test to confirm the clinical diagnosis of A-T. Colony-survival assay (CSA) and radioresistant DNA synthesis have been validated for clinical diagnostic testing and CSA was reported to be one of the most reliable assays to identify A-T patients [1], when tested in experienced laboratories.…”

Section: Ataxia Telangiectasia a Representative Xcind Diseasementioning

confidence: 99%

“…But evaluating sensitivity to X-IRinduced DNA damage requires substantial experience. Instead of employing CSA, we can also use a foci formation assay for cH2AX, 53BP1, or BRCA1 as surrogate marker, which is called the irradiation-induced foci (IRIF) kinetics method [1].…”

Section: Introductionmentioning

confidence: 99%

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

Mizutani

Takagi

2012

Int J Hematol

View full text Add to dashboard Cite

The XCIND syndrome is named after distinct hypersensitivity to ionizing (X-ray) irradiation, cancer susceptibility, immunodeficiency, neurological abnormality, and double-strand DNA breakage. The disorders comprising XCIND syndrome are usually inherited in an autosomal recessive manner. Ataxia telangiectasia (A-T) is one such disease, and is caused by biallelic germline mutation of the Ataxia telangiectasia mutated (ATM) gene. Heterozygous carriers of the ATM mutation, who do not show A-T-like clinical symptoms, are estimated to comprise 1 % of the population. Thus, understanding the biological basis of XCIND, including A-T, should help shed light on the pathogenesis of genetic diseases with cancer susceptibility.

show abstract

Assessing ‘radiosensitivity’ with kinetic profiles of γ-H2AX, 53BP1 and BRCA1 foci

Cited by 30 publications

References 32 publications

DNA damage response and hematological malignancy

DNA damage response and hematological malignancy

SMRT compounds abrogate cellular phenotypes of ataxia telangiectasia in neural derivatives of patient-specific hiPSCs

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

Contact Info

Product

Resources

About