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Abstract

Summary ATM (ataxia-telangiectasia mutated) gene plays a central role in the DNA-damage response pathway. We characterized the ATM protein expression in immortalized cells from AT and AT-variant patients, and heterozygotes and correlated it with two ATM-dependent radiation responses, G1 checkpoint arrest and p53-Ser 15 phosphorylation. On Western blots, the full-length ATM protein was detected in eight of 18 AT cases, albeit at 1-32% of the normal levels, whereas a truncated ATM protein was detected in a single case, despite the prevalence among cases of truncation mutations. Of two ataxia without telangiectasia [A-(T)] cases, one expressed 20% and the other ~70% of the normal ATM levels. Noteworthy, among ten asymptomatic heterozygous carriers for AT, normal amounts of ATM protein were found in one and reduced by 40-50% in the remaining cases. The radiation-induced phosphorylation of p53 protein at serine 15, largely mediated by ATM kinase, was defective in AT, A(-T) and in 2/4 heterozygous carriers, while the G1 cell cycle checkpoint was disrupted in all AT and A(-T) cases, and in 3/10 AT heterozygotes. Altogether, our study shows that AT and A(-T) cases bearing truncation mutations of the ATM gene can produce modest amounts of full-length (and only rarely truncated) ATM protein. However, this limited expression of ATM protein provides no benefit regarding the ATM-dependent responses related to G1 arrest and p53-ser15 phosphorylation. Our study additionally shows that the majority of AT heterozygotes express almost halved levels of ATM protein, sufficient in most cases to normally regulate the ATM-dependent DNA damage-response pathway.

Actionable perturbations of damage responses by TCL1/ATM and epigenetic lesions form the basis of T-PLL

“…The A-T patient-derived B-lymphoblastoid cell lines 73 ‘AT65RM’ (ATM Δ/Δ : c.6573-9G->A/ c.8814_8824del11; ATM protein absent) and ‘AT-CT’ ( ATM WT control from an unaffected relative) were used to assess (ATM related) specificity of pKAP Ser824 induction.…”

Quantitative Proteomics Identifies DNA Repair as a Novel Biological Function for Hepatocyte Nuclear Factor 4α in Colorectal Cancer Cells

“…Transcription factors can affect DNA repair indirectly by regulating the expression of genes encoding components of different DNA repair pathways [18]. Probably the best-characterized example is the initiation of the transactivation activity of p53 transactivation activity through the phosphorylation of its serine 20 by CHK2 and CHK1 and of its serine 15 by ATM/ATR [19,20]. The latter are important DNA damage sensors and can also regulate MDM2 degradation by ubiquitination, resulting in the stabilization of p53 [21].…”