Ataxia-telangiectasia: una revisión desde la etiopatogenia al manejo actual con descripción de casos reportados en Perú / Ataxia telangiectasia: A review from etiopathogenesis to current management with a description of reported cases in Peru

La Ataxia-Telangiectasia (AT) es una rara enfermedad de herencia autosómica recesiva y de afección multisistémica, caracterizada por ataxia progresiva, inmunodeficiencia variable con infecciones recurrentes, riesgo incrementado de neoplasias con o sin telangiectasias óculo-cutáneas. La AT es causada por variantes patogénicas bialélicas en el gen ATM. Su diagnóstico se basa en la sospecha de un cuadro clínico compatible, niveles elevados de alfafetoproteína, atrofia cerebelosa y estudios genéticos. No existe tratamiento curativo de AT y su manejo se basa en medidas de soporte y prevención de complicaciones y asesoramiento genético. En esta revisión, actualizamos la epidemiología, manifestaciones clínicas, diagnóstico y tratamiento de AT incluyendo una búsqueda de casos publicados en el Perú.

Ataxia-Telangiectasia (AT) is a rare autosomal recessive disease with multisystemic involvement, characterized by slowly progressive ataxia, variable immunodeficiency with recurrent infections, increased risk of neoplasms with or without oculocutaneous telangiectasias. AT is caused by biallelic pathogenic variants within the ATM gene. Its diagnosis is based on suspicion of a compatible clinical symptomatology, increased levels of alpha-fetoprotein, cerebellar atrophy, and genetic testing. There is no curative treatment for AT and its management is based on supportive and preventive measures of eventual complications and genetic counseling. This review updates the epidemiology, clinical manifestations, diagnosis, and treatment of AT, including a search for cases published in Peru.

Virtual screening of potential ATR kinase inhibitors based on machine learning and molecular docking / 中国药科大学学报

@#Screening potential active compounds from molecular libraries is a common method for drug discovery.However, with the continuous exploration of chemical space, there are already compound libraries with more than billions of molecules, so molecular docking is no longer enough to quickly screen specific target inhibitors from the ultra-large compound libraries.This study proposes a method for screening potential active compounds, which involves filtering and selecting compounds from a candidate compound library containing over 5.5 billion molecules through a series of steps, including calculating physical and chemical property similarities, constructing machine learning prediction models, and molecular docking.In the end, 51 compounds with potential ataxia telangiectasia-mutated and rad3-related (ATR) inhibitory activity were obtained.This method is effective for rapidly screening novel potential active compounds from large compound libraries.

Radiation-induced Hierarchical Topologically Associated Domain Change and Its Role in Cellular Responses to Radiation / 中国生物化学与分子生物学报

The three-dimensional (3D) genome organization plays an important role in gene regulation. As a basic functional unit of the genome, topologically associated domain (TAD) regulates multiplebiological processes such as gene expression and DNA replication and plays a role in radiation-inducedDNA damage repair. Recent studies showed that TAD is not a completely independent domain butcontains hierarchical internal domains, which could be a new mechanism of gene regulation. To explorethe role of hierarchical TAD in cellular responses to radiation, we apply the OnTAD algorithm, anoptimized nested TAD caller from Hi-C data, to identify hierarchical TAD in 26 Hi-C data from Geneexpression omnibus (GEO) database. These data were from irradiated fibroblasts, lymphoblasts andfibroblasts deficient in the ataxia telangiectasia mutated (ATM) gene with 5 Gy X-ray. We observe thatX-ray can regularly affect the hierarchy of TAD in which high-level TAD is prone to change and low-levelTAD is more conservative. We propose that radiation-induced TAD hierarchy change can regulate cellularresponses to radiation by regulating gene expression, and ATM is a necessary factor for radiation-inducedTAD hierarchy change and recovery. This study provides new insights into the role of the 3D genome inradiation-induced cellular responses from the perspective of hierarchical TAD structures.

Role of ataxia-telangiectasia mutated gene in maintaining quiescence of neural stem cell from subgranular zone of mouse hippocampus / 解剖学报

Objective To investigate the role of ataxia-telangiectasia mutated gene (ATM) in maintaining quiescence of neural stem cells (NSCs) from subgranular zone (SGZ) of hippocampal dentate gyms in mice. Methods We constructed 1-month-old and 4-month-old mice ATM knockout mice, with 12 mice in each group. The NSCs in SGZ of ATM knockout mice were isolated, cultured and identified in vitro. The proliferation ability of NSCs in SGZ of 1-month-old ATM

Chemical screen identifies shikonin as a broad DNA damage response inhibitor that enhances chemotherapy through inhibiting ATM and ATR

DNA damage response (DDR) is a highly conserved genome surveillance mechanism that preserves cell viability in the presence of chemotherapeutic drugs. Hence, small molecules that inhibit DDR are expected to enhance the anti-cancer effect of chemotherapy. Through a recent chemical library screen, we identified shikonin as an inhibitor that strongly suppressed DDR activated by various chemotherapeutic drugs in cancer cell lines derived from different origins. Mechanistically, shikonin inhibited the activation of ataxia telangiectasia mutated (ATM), and to a lesser degree ATM and RAD3-related (ATR), two master upstream regulators of the DDR signal, through inducing degradation of ATM and ATR-interacting protein (ATRIP), an obligate associating protein of ATR, respectively. As a result of DDR inhibition, shikonin enhanced the anti-cancer effect of chemotherapeutic drugs in both cell cultures and in mouse models. While degradation of ATRIP is proteasome dependent, that of ATM depends on caspase- and lysosome-, but not proteasome. Overexpression of ATM significantly mitigated DDR inhibition and cell death induced by shikonin and chemotherapeutic drugs. These novel findings reveal shikonin as a pan DDR inhibitor and identify ATM as a primary factor in determining the chemo sensitizing effect of shikonin. Our data may facilitate the development of shikonin and its derivatives as potential chemotherapy sensitizers through inducing ATM degradation.

Expression and functional SNP loci screen of ATM from coal worker's pneumoconiosis / 中华劳动卫生职业病杂志

Objective: To detect of gene expression and genotype of the ataxia telangiectasia mutated (ATM) from coal workers' pneumoconiosis (CWP) , It is explored whether CWP is related to ATM gene. Methods: In October 2020, the relevant information of 264 subjects who received physical examination or medical treatment in the Department of occupational diseases of Guiyang public health treatment center from January 2019 to September 2020 was collected. Through the occupational health examination, 67 healthy people with no history of exposure to occupational hazards were selected as the healthy control group; The coal miners with more than 10 years of coal dust exposure history and small shadow in the lung but not up to the diagnostic criteria were the dust exposure control group, a total of 66 people; The patients with the same history of coal dust exposure and confirmed stage I were coal worker's pneumoconiosis stage I group, a total of 131 people. The expression of ATM was detected by QRT PCR. ATM rs189037 and rs1801516 were genotyped by massarray. Results: There was significant difference in the expression of ATM among the groups (P<0.05) ; Compared with the healthy control group, the expression of ATM in the dust exposed control group was significantly increased (P<0.05) . With the occurrence and development of CWP, the GG of rs189037 wild type decreased, the GA of mutant heterozygote and AA of homozygote increased, but the difference was not statistically significant (P>0.05) ; Rs1801516 wild type GG and mutant heterozygote GA had no significant changes (P>0.05) . There were significant differences in age, neutrophils and basophils among rs189037 groups (all P<0.05) . There were no significant differences in blood pressure, eosinophils, lymphocytes, monocytes, smoking and drinking history among rs189037 groups (all P>0.05) . Compared with wild-type GG, the or of mutant heterozygotes and homozygotes increased, but the differences were not statistically significant (P>0.05) . Conclusion: ATM gene may be one of the early activation genes of CWP and rs189037 may be the functional loci which affects gene expression. ATM gene is related to inflammatory response, Neutrophils and basophils have an impact on the development of CWP.

Correlation analysis between ATM gene polymorphism and susceptibility of sporadic breast cancer / 中国医师杂志

Objective:To analyze the relationship between ataxia telangiectasia mutated (ATM) single nucleotide polymorphism (SNP) at rs1801516 and rs1800054 and sporadic breast cancer (SBC) in Inner Mongolia.Methods:A total of 102 patients with SBC (72 Han and 30 Mongolian) who were admitted to the Affiliated Hospital of Inner Mongolia Medical University from January 2018 to September 2019 were prospectively collected as case group and 102 healthy women (72 Han and 30 Mongolian) during the same period as control group. 2 ml of venous blood was collected to extract DNA. According to the Single Nucleotide Polymorphism Database (dbSNP), the highly polymorphic sites rs1801516 and rs1800054 of ATM gene were selected. The polymerase chain reaction (PCR) and direct sequencing were used to detect the polymorphism of the two sites, and the correlation between the single nucleotide polymorphism of the two sites and the susceptibility of SBC in Inner Mongolia was analyzed. The potential association between clinicopathological factors and ATM gene polymorphism in patients with SBC in Inner Mongolia were explored.Results:GG, GA and AA genotypes were detected in rs1801516 locus of ATM gene. Only CC genotype was detected in the rs1800054 locus of ATM gene. There was no significant difference in the distribution of genotype frequency and allele frequency between Mongolian breast cancer group and Han breast cancer group, Mongolian control group and Han control group, Mongolian breast cancer group and Mongolian control group, Han breast cancer group and Han control group (all P>0.05). Logistic regression analysis showed that allele G was the susceptibility gene of SBC in Inner Mongolia ( OR: 1.775, 95% CI: 1.04-3.03, P=0.04). ATM rs1801516 polymorphism may be associated with increased risk of breast cancer in patients with mass diameter ≤2 cm and/or without lymph node metastasis (all P<0.05). Conclusions:The polymorphism of ATM gene rs1801516 and rs1800054 may not be significantly correlated with the risk of SBC in Inner Mongolia. The rs1801516 locus may be associated with increased risk of breast cancer in patients with mass diameter ≤2 cm and/or without lymph node metastasis. Gene G may be one of the susceptible genes of SBC in Inner Mongolia.

Phosphorylation regulates cullin-based ubiquitination in tumorigenesis

Cullin-RING ligases (CRLs) recognize and interact with substrates for ubiquitination and degradation, and can be targeted for disease treatment when the abnormal expression of substrates involves pathologic processes. Phosphorylation, either of substrates or receptors of CRLs, can alter their interaction. Phosphorylation-dependent ubiquitination and proteasome degradation influence various cellular processes and can contribute to the occurrence of various diseases, most often tumorigenesis. These processes have the potential to be used for tumor intervention through the regulation of the activities of related kinases, along with the regulation of the stability of specific oncoproteins and tumor suppressors. This review describes the mechanisms and biological functions of crosstalk between phosphorylation and ubiquitination, and most importantly its influence on tumorigenesis, to provide new directions and strategies for tumor therapy.

Alterations of DNA damage response pathway: Biomarker and therapeutic strategy for cancer immunotherapy

Genomic instability remains an enabling feature of cancer and promotes malignant transformation. Alterations of DNA damage response (DDR) pathways allow genomic instability, generate neoantigens, upregulate the expression of programmed death ligand 1 (PD-L1) and interact with signaling such as cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling. Here, we review the basic knowledge of DDR pathways, mechanisms of genomic instability induced by DDR alterations, impacts of DDR alterations on immune system, and the potential applications of DDR alterations as biomarkers and therapeutic targets in cancer immunotherapy.

Association between single nucleotide polymorphism at rs175048 locus of ATM gene and susceptibility to lung cancer in Han population in Hengyang, Hunan / 中国肿瘤生物治疗杂志

@# Objective: To explore the association between the single nucleotide polymorphism (SNP) of rs175048 in ataxia telangiectasia mutated (ATM) gene and lung cancer susceptibility in Han population. Methods: A total of 225 cases of blood samples from lung cancer patients treated in Hospital of Traditional Chinese Medicine of Hengyang City and the Affiliated First Hospital of Nanhua University from October 2015 to August 2016 were collected as case group, and 128 cases of blood samples from healthy people were collected as the control. The polymorphisms of ATM rs175048 of above mentioned participants were detected by using the SNP sensitive On/Off Switch technique. The genotypes and allele frequencies were analyzed to compare the distribution difference between case group and control group as well as its association to the clinical features of lung cancer. Results: The genotype frequencies of AA, AT and TT of ATM rs175048 were 24.9%, 52.9%, 22.2% in case group and 42.2%, 42.2%, 15.6% in control group, respectively (all P< 0.01). Moreover, the frequencies of alleles A and T were 51.0%, 49.0% in case group, and 63.0%, 37.0% in control group (all P<0.01). Genotype TT might increase while genotype AT might decrease the risk of lung cancer. rs175048 SNP was significantly correlated with smoking, age, sex and family history (all P<0.05). Conclusion: rs175048 SNPis significantly associated with lung cancer, and TT genotype may increase the risk of lung cancer.

Research progress on ataxia-telangiectasia / 国际儿科学杂志

Ataxia-telangiectasia (AT) is a rare autosomal recessive genetic disorder resulting from ataxia-telangiectasia mutated (ATM) gene mutation.ATM involved in DNA repair.ATM is made up of 66 exons.Its mutation forms are complex,including nonsense mutation,missense mutation,shear site mutation,insertion and deletion,etc.The patients are characterized by progressive cerebellar atrophy and ataxia,disturbance of eye movement,telangiectasia and dystonia,a high risk of cancer and immunodeficiency.These patients are also hypersensitive to radiotherapy.AT is often neglected at the early stage.As pediatricians,we should pay attention to early ataxia and conduct genetic testing as early as possible to avoid radiation exposure.

Research progress on ataxia-telangiectasia / 国际儿科学杂志

Ataxia-telangiectasia (AT) is a rare autosomal recessive genetic disorder resulting from ataxia-telangiectasia mutated(ATM) gene mutation.ATM involved in DNA repair.ATM is made up of 66 exons.Its mutation forms are complex, including nonsense mutation, missense mutation, shear site mutation, insertion and deletion, etc.The patients are characterized by progressive cerebellar atrophy and ataxia, disturbance of eye movement, telangiectasia and dystonia, a high risk of cancer and immunodeficiency.These patients are also hypersensitive to radiotherapy.AT is often neglected at the early stage.As pediatricians, we should pay attention to early ataxia and conduct genetic testing as early as possible to avoid radiation exposure.

A Novel Homozygous Variant of SETX Causes Ataxia with Oculomotor Apraxia Type 2

BACKGROUND AND PURPOSE: Autosomal recessive cerebellar ataxias constitute a highly heterogeneous group of neurodegenerative disorders. This study was carried out to determine the clinical and genetic causes of ataxia in two families from Pakistan. METHODS: Detailed clinical investigations were carried out on probands in two consanguineous families. Magnetic resonance imaging was performed. Exome sequencing data were examined for likely pathogenic variants. Candidate variants were checked for cosegregation with the phenotype using Sanger sequencing. Public databases including ExAC, GnomAD, dbSNP, and the 1,000 Genome Project as well as ethnically matched controls were checked to determine the frequencies of the alleles. Conservation of missense variants was ensured by aligning orthologous protein sequences from diverse vertebrate species. RESULTS: Reverse phenotyping identified spinocerebellar ataxia, autosomal recessive 1 [OMIM 606002, also referred to as ataxia oculomotor apraxia type 2 (AOA2)] and ataxia telangiectasia (OMIM 208900) in the two families. A novel homozygous missense mutation c.202 C>T (p.Arg68Cys) was identified within senataxin, SETX in the DNA of both patients in one of the families with AOA2. The patients in the second family were homozygous for a known variant in ataxia-telangiectasia mutated (ATM) gene: c.7327 C>T (p.Arg2443Ter). Both variants were absent from 100 ethnically matched control chromosomes and were either absent or present at very low frequencies in the public databases. CONCLUSIONS: This report extends the allelic heterogeneity of SETX mutations causing AOA2 and also presents an asymptomatic patient with a pathogenic ATM variant.

Ataxia-Telangiectasia-Mutated Protein Expression as a Prognostic Marker in Adenoid Cystic Carcinoma of the Salivary Glands

PURPOSE: Adenoid cystic carcinoma (ACC) is a high-grade malignant tumor of the salivary glands, clinically characterized by multiple recurrences and late distant metastasis. Biological markers for assessing the prognosis of ACC have remained elusive. The purpose of this study was to investigate whether the protein expressions of ataxia telangiectasia mutated (ATM), p53, and ATM-mediated phosphorylated p53 are related to patient survival in ACC. MATERIALS AND METHODS: In this study, 48 surgical samples were used to assess the expressions of ATM and its downstream target p53. Fisher's exact test and Kaplan-Meier analysis were conducted to evaluate the role of ATM, p53, and phospho-p53 (S15) protein expressions in predicting patient survival and distant metastasis. RESULTS: Myb expression was positive in 85.4% of ACCs, but did not reflect patient survival rate. In contrast, low expression of ATM in cancer cells was significantly correlated with poor survival rate (p=0.037). Moreover, under positive p53 expression, low expression of ATM was highly predictive of poor survival in ACC (p=0.017). CONCLUSION: These data indicate that combined assessment of ATM and p53 expression can serve as a useful prognostic marker for assessing survival rate in patients with ACC of the salivary glands.

Ataxia-telangiectasia mutated gene-silencing inhibits the migration and invasion of human breast cancer cells / 肿瘤

Objective: To investigate the effects of ataxia-telangiectasia mutated (ATM) gene-silencing on the proliferation, migration and invasion of human triple-negative breast cancer MDA-MB-231 cells. Methods: The recombinant lentiviral vectors with ATM gene-targeted specific shRNA or the negative control sequence (as the negative control group) were infected into the human triple-negative breast cancer MDA-MB-231 cells to obtain the ATM gene-silencing cells. At the same time, the uninfected MDA-MB-231 cells was used as the blank control group. After screening by puromycin, the infection efficiency of each group was observed under a fluorescence microscope. The expressions of ATM mRNA and protein in MDA-MB-231 cells in the three groups were detected by real-time fluorescent quantitative PCR and Western blotting, respectively. The effects of ATM gene-silencing on proliferation, cycle distribution, migration and invasion of MDA-MB-231 cells were analyzed by MTT method, FCM, cell wound healing assay and Transwell assays, respectively. Results: The human triple-negative breast cancer MDA-MB-231 cells with stable ATM genesilencing were established successfully. Compared with the blank control and negative control groups, the proliferation and cell cycle distribution of MDA-MB-231 cells in ATM gene-silencing group had no significant change (all P > 0.05), but the migration and invasion abilities of MDA-MB-231 cells in ATM gene-silencing group were decreased significantly (all P<0.05). Conclusion: The down-regulation of ATM gene expression can significantly inhibit the migration and invasion of human triple-negative breast cancer MDA-MB-231 cells.

ATM polymorphisms IVS24-9delT, IVS38-8T>C, and 5557G>A in Mexican women with familial and/or early-onset breast cancer / Polimorfismos IVS24-9delT, IVS38-8T>C y 5557G>A en el gen ATM en mujeres mexicanas con cáncer de mama familiar o de inicio temprano

Objective. To assess whether in Mexican population the frequencies of ATM polymorphisms IVS24-9delT, IVS38-8-T>C, and 5557G>A in breast cancer (BC) cases and healthy controls were different from those found in other countries. Materials and methods. Frequencies of polymorphisms conferring BC risk IVS24-9delT, IVS38-8T>C, and 5557G>A were analyzed by PCR-RFLP in 94 patients with familial and/or early onset BC, and 97 healthy controls randomly selected. Allele frequencies analysis was done using χ² and Hardy-Weinberg test. Results. Frequencies of heterozygous were: for 5557G>A, 13% cases, 0%controls (p=0.0009); for IVS24-9delT, 21% cases, 8% controls (p=0.0122); for IVS38-8T>C, only one case. 5557G>A and IVS24-9delT were more frequent in cases than in controls. The allelic frequencies found in 5557G>A are similar to those described by González-Hormazábal in Chile. Conclusion. The similarity of results in this polymorphism between Chilean and Mexican populations may be due to both being crossbred with an Amerindian-Spanish component, while differences may be due to fact that Chilean population has a greater European component than Mexican's.

Objetivo. Evaluar si en la población mexicana las frecuencias de los polimorfismos IVS-9delT, IVS38-8T>C y 5557G>A en casos de cáncer de mama y en controles sanos son diferentes de las encontradas en otros países. Material y métodos. Los polimorfismos IVS24-9delT, IVS38-8T>C y 5557G>A fueron analizados mediante PCR-RFLPs en 94 pacientes con CM de tipo familiar o de inicio temprano y 97 testigos seleccionadas de forma aleatoria. El análisis de la frecuencia alélica se hizo mediante χ² y equilibrio de Hardy-Weinberg. Resultados. Las frecuencias de heterocigotos fueron 5557G>A, 13% de casos, 0% de testigos (p=0.0009); IVS24-9delT, 21% de casos, 8% de testigos (p=0.0l22); IVS38-8T>C, sólo un caso. 5557G>A y IVS24-9delT fueron más frecuentes en casos que en testigos. Las frecuencias alélicas encontradas en 5557G>A son similares a las descritas por González-Hormazábal en Chile. Conclusión. La similitud de resultados en este polimorfismo entre la población chilena y mexicana puede ser debida a que ambas son mestizas con un componente amerindio-español. Las diferencias encontradas podrían explicarse porque la población chilena tiene mayor componente europeo que la mexicana.

Effect of silencing of ATM expression by siRNA on radiosensitivity of human lung adenocarcinoma A549 cells / 中华放射肿瘤学杂志

Objective To investigate the effect of silencing of ataxia-telangiectasia mutated (ATM) expression by plasmid-mediated RNA interference on the radiosensitivity of human lung adenocarcinoma A549 cells.Methods Eukaryotic expression plasmid containing ATM small interfering RNA (siRNA) (pSilencer2.1-ATM),as well as pSilencer2.1-nonspecific,was constructed.Lung adenocarcinoma A549 cells were divided into positive group,negative group,and control group to be transfected with pSilencer2.1-ATM,pSilencer2.1-nonspecific,and no plasmid,respectively.The mRNA and protein expression of ATM was measured by RT-PCR and Western blot,respectively.The change in cell radiosensitivity was observed by colony-forming assay.Cell cycle and cell apoptosis were analyzed by flow cytometry.Results The eukaryotic expression plasmid containing ATM siRNA was successfully constructed.The RT-PCR and Western blot demonstrated that the expression of ATM was down-regulated in the positive group.The sensitization enhancement ratios (D0 ratios) for the positive group and negative group were 1.50 and 1.01,respectively.The flow cytometry revealed that the proportions of A549 cells in G1 and G2/M phases were significantly lower in the positive group than in the control group (51.27％ vs 61.85％,P =0.012;6.34％ vs 10.91％,P =0.008) and that the apoptosis rate was significantly higher in the positive group than in the control group and negative group (49.31％ vs 13.58％,P=0.000;49.31％ vs 13.17％,P=0.000).Conclusions Silencing of ATM expression may increase the radiosensitivity of human lung adenocarcinoma A549 cells,probably by affecting the cell cycle and promoting cell apoptosis.

Identification of ATM Mutations in Korean Siblings with Ataxia-Telangiectasia

Ataxia-telangiectasia (A-T) is a rare autosomal recessive neurodegenerative disorder. It is characterized by early-onset, progressive cerebellar ataxia, oculomotor apraxia, choreoathetosis, conjunctival telangiectasias, immunodeficiency, and an increased risk of malignancy. Although A-T is known to be the most common cause of progressive cerebellar ataxia in childhood, there have been no confirmed cases in Korea. We report the clinical and genetic findings of Korean siblings who presented with limb and truncal ataxia, oculomotor apraxia, choreoathetosis, and telangiectasias of the eyes. Sequence analysis of the ataxia-telangiectasia mutated (ATM) gene revealed a known missense mutation (c.8546G>C; p.Arg2849Pro) and a novel intronic variant of intron 17 (c.2639-19_2639-7del13). Reverse-transcription PCR and sequencing analysis revealed that the c.2639-19_2639-7del13 variant causes a splicing aberration that potentiates skipping exon 18. Because A-T is quite rare in Korea, the diagnosis of A-T in Korean patients can be delayed. We recommend that a diagnosis of A-T should be suspected in Korean patients exhibiting the clinical features of A-T.

Identification of ATM Mutations in Korean Siblings with Ataxia-Telangiectasia

Ataxia-telangiectasia (A-T) is a rare autosomal recessive neurodegenerative disorder. It is characterized by early-onset, progressive cerebellar ataxia, oculomotor apraxia, choreoathetosis, conjunctival telangiectasias, immunodeficiency, and an increased risk of malignancy. Although A-T is known to be the most common cause of progressive cerebellar ataxia in childhood, there have been no confirmed cases in Korea. We report the clinical and genetic findings of Korean siblings who presented with limb and truncal ataxia, oculomotor apraxia, choreoathetosis, and telangiectasias of the eyes. Sequence analysis of the ataxia-telangiectasia mutated (ATM) gene revealed a known missense mutation (c.8546G>C; p.Arg2849Pro) and a novel intronic variant of intron 17 (c.2639-19_2639-7del13). Reverse-transcription PCR and sequencing analysis revealed that the c.2639-19_2639-7del13 variant causes a splicing aberration that potentiates skipping exon 18. Because A-T is quite rare in Korea, the diagnosis of A-T in Korean patients can be delayed. We recommend that a diagnosis of A-T should be suspected in Korean patients exhibiting the clinical features of A-T.

p53 and DNA-dependent protein kinase catalytic subunit independently function in regulating actin damage-induced tetraploid G1 arrest

We previously reported that the p53 tumor suppressor protein plays an essential role in the induction of tetraploid G1 arrest in response to perturbation of the actin cytoskeleton, termed actin damage. In this study, we investigated the role of p53, ataxia telangiectasia mutated protein (ATM), and catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) in tetraploid G1 arrest induced by actin damage. Treatment with actin-damaging agents including pectenotoxin-2 (PTX-2) increases phosphorylation of Ser-15 and Ser-37 residues of p53, but not Ser-20 residue. Knockdown of ATM and DNA-PKcs do not affect p53 phosphorylation induced by actin damage. However, while ATM knockdown does not affect tetraploid G1 arrest, knockdown of DNA-PKcs not only perturbs tetraploid G1 arrest, but also results in formation of polyploidy and induction of apoptosis. These results indicate that DNA-PKcs is essential for the maintenance of actin damage induced-tetraploid G1 arrest in a p53-independent manner. Furthermore, actin damage-induced p53 expression is not observed in cells synchronized at G1/S of the cell cycle, implying that p53 induction is due to actin damage-induced tetraploidy rather than perturbation of actin cytoskeleton. Therefore, these results suggest that p53 and DNA-PKcs independently function for tetraploid G1 arrest and preventing polyploidy formation.