PubMed Health⌕ Search
Home/Archive/PubMed

PubMed · 15473314

[ATM and telomere instability].

Hong-Mei Wang·Yun-Fei Xia·Xin-Yao Wu
View original source ↗Export metadata ↓

Abstract

Accumulation of DNA damage has been associated with the onset of senescence and the predisposition to cancer. The gene responsible for ataxia telangiectasia (A-T) is ATM (Ataxia-telangiectasia mutant), a master controller of cellular pathways and networks, orchestrating the response to a specific type of DNA damage, i.e., the double strand break. It has now been demonstrated that mutations in ATM lead to defective telomere maintenance in mammalian cells. This review will focus on its roles in telomere metabolism and how ATM and telomeres serve as controllers of cellular responses to DNA damage.

Explore related subjects

Ataxia TelangiectasiaAtaxia Telangiectasia Mutated ProteinsCell Cycle ProteinsChromosomal InstabilityDNA DamageDNA-Binding ProteinsHumansProtein Serine-Threonine KinasesSignal TransductionTelomeraseTelomereTumor Suppressor ProteinsJournal ArticleResearch Support, Non-U.S. Gov'tReview

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Hong-Mei Wang, Yun-Fei Xia, Xin-Yao Wu. 2004. [ATM and telomere instability].. https://pubmed.ncbi.nlm.nih.gov/15473314/

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related citations

PubMed2008

Papillary thyroid carcinoma in a 9-year-old girl with ataxia-telangiectasia.

A 9-year-old female with ataxia-telangiectasia (AT) presenting with papillary thyroid carcinoma and lymph nodes involvement is reported. We discuss this novel association, the general risk of neoplasic complications in these patients, the natural history of thyroid carcinoma in the pediatric population and the potential link between thyroid carcinogenesis and ataxia-telangiectasia mutated gene (ATM) mutation. We also expose our therapeutic attitude, according to both clinical status and particular genetic background of our patient.

Ataxia Telangiectasia↗
PubMed2006

ATM-mediated response to DNA double strand breaks in human neurons derived from stem cells.

Ataxia-telangiectasia (A-T) is a multi-system genomic instability syndrome that is caused by loss or inactivation of the ATM protein kinase. ATM is largely nuclear in proliferating cells, and activates an extensive network of pathways in response to double strand breaks (DSBs) in the DNA by phosphorylating key proteins in these pathways. The prominent symptom of A-T is neuronal degeneration, making the elucidation of ATM's functions in neurons essential to understanding the disease. It has been suggested that ATM is cytoplasmic in neurons and functions in processes that are not associated with the DNA damage response. Recently we showed that in human neuron-like cells obtained by in vitro differentiation of neuroblastomas, ATM was largely nuclear and mediated the DSB response as in proliferating cells. We have now extended these studies to two additional model systems: neurons derived from human embryonic stem cells, and cortical neurons derived from neural stem cells. The results substantiate the notion that ATM is nuclear in human neurons and mediates the DSB response, the same as it does in proliferating cells. We present here unique and powerful model systems to further study the ATM-mediated network in neurons.

Ataxia Telangiectasia↗
PubMed2006

Evaluation of the role of Finnish ataxia-telangiectasia mutations in hereditary predisposition to breast cancer.

Biallelic mutations in the ataxia-telangiectasia mutated (ATM) gene result in ataxia-telangiectasia (A-T). Studies on A-T families have shown that obligate female carriers have increased risk of developing breast cancer. Here we have evaluated the role of known Finnish ATM germ line mutations as possible breast cancer predisposing alleles outside A-T families by analyzing their prevalence in large cohorts of familial and unselected breast cancer cases. Of seven different alterations, two were observed in the studied breast cancer material. ATM 6903insA (causing protein truncation) was seen in 3/541 familial and 5/1124 unselected cases, but not among healthy population controls (0/1107). 7570G>C (Ala2524Pro) occurred in 1/541 familial and 2/1124 unselected cases compared with 1/1107 in controls. Additionally, 8734A>G (Arg2912Gly) associated previously with breast cancer susceptibility and suggested to be causative also for A-T was detected in 2/541 of familial cases, but not in unselected cases (0/1124) or controls (0/1107). In total, heterozygous ATM mutation carriers were observed in 6/541 familial [P = 0.006, odds ratio (OR) 12.4, 95% confidence interval (CI) 1.5-103.3) and 7/1124 unselected cases (P = 0.07, OR 6.9, 95% CI 0.9-56.4), compared with 1/1107 in controls, suggesting an apparent yet overall limited contribution to predisposition to cancer. The current results also provided evidence for founder effects in the geographical distribution of these mutations. Interestingly, results from functional analysis of the breast cancer-associated ATM mutations indicated that cancer susceptibility is not restricted to mutations with dominant-negative effect on kinase activity, displayed only by 7570G>C, whereas 8734A>G showed only a partial defect in the phosphorylation of ATM substrates, and 6903insA seemed to be a null allele.

Ataxia Telangiectasia↗