Ataxia-telangiectasia: from a rare disorder to a paradigm for cell signalling and cancer

Lavin, Martin F.

doi:10.1038/nrm2514

Cited by 816 publications

(729 citation statements)

References 114 publications

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“…Following the exposure to genotoxic agents, the serine/threonine kinase ATM directly and indirectly phosphorylates several substrates in order to orchestrate the cellular DNA-damage response (DDR), activating a signaling cascade which induces DNA repair, cell-cycle checkpoint activation and, eventually, apoptosis or senescence (Lavin, 2008). Interestingly, ATM-deficient cells display an increased sensitivity to genotoxic agents (Meyn et al, 1994;Savitsky et al, 1995;Ku¨hne et al, 2004), and chemical inhibition of ATM induces cellular chemo-and radio-resistance (Sarkaria et al, 1998(Sarkaria et al, , 1999Sarkaria and Eshleman 2001).…”

Section: Introductionmentioning

confidence: 99%

HMGA proteins promote ATM expression and enhance cancer cell resistance to genotoxic agents

et al. 2011

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DNA-damaging therapies represent a keystone in cancer treatment. Unfortunately, many tumors often relapse because of a group of cancer cells, which are resistant to conventional therapies. High-mobility group A (HMGA) proteins has a key role in cell transformation, and their overexpression is a common feature of human malignant neoplasias, representing a poor prognostic index often correlated to anti-cancer drug resistance. Our previous results demonstrated that HMGA1 is a substrate of ataxiatelangiectasia mutated (ATM), the main cellular sensor of genotoxic stress. Here we also report thatHMGA2, the other member of the HMGA family, is a novel substrate of ATM. Interestingly, we found that HMGA proteins positively regulate ATM gene expression. Moreover, induction of ATM kinase activity by DNA-damaging agents enhances HMGA-dependent transcriptional activation of ATM promoter, suggesting that ATM expression is modulated by a DNA-damage-and HMGA-dependent positive feedback loop. Finally, inhibition of HMGA expression in mouse embryonic fibroblasts and in cancer cells strongly reduces ATM protein levels, impairing the cellular DNA-damage response and enhancing the sensitivity to DNA-damaging agents. These findings indicate this novel HMGA-ATM pathway as a new potential target to improve the effectiveness of conventional anti-neoplastic treatments on the genotoxic-drug resistant cancer cells.

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Section: Introductionmentioning

confidence: 99%

HMGA proteins promote ATM expression and enhance cancer cell resistance to genotoxic agents

et al. 2011

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“…In fact, in response to DSB induction, H2AX is phosphorylated at the Ser139 residue (the phosphorylated H2AX protein being named c-H2AX) by members of the phosphoinositide-3-kinase-related protein kinase family [e.g., ataxia-telangiectasia-mutated (ATM) kinase and the DNAdependent kinase (DNA-PK)] (6). The p53 binding protein 1 (53BP1) functions downstream of a c-H2AX-dependent hierarchy of proteins (e.g., the MRN complex, ATM, and the media-tor of DNA-damage checkpoint 1 protein (MDC1)) that collectively establish IRIF at DSB sites (7)(8)(9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

Cleavage of the BRCT tandem domains of nibrin by the 657del5 mutation affects the DNA damage response less than the Arg215Trp mutation

et al. 2012

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SummaryThe Nijmegen breakage syndrome (NBS) is a genetic disorder caused by mutations in NBN gene and characterized by chromosomal instability and hypersensitivity to ionizing radiations (IR). The N-terminus of nibrin (NBN) contains a tandem breast cancer 1 (BRCA1) carboxy-terminal (BRCT) domain that represents one of the major mediators of phosphorylation-dependent protein-protein interactions in processes related to cell cycle checkpoint and DNA repair functions. Patients with NBS compound heterozygous for the 657del5 hypomorphic mutation and for the Arg215Trp missense mutation (corresponding to the 643C[T gene mutation) display a clinical phenotype more severe than that of patients homozygous for the 657del5 mutation. Here, we show that both the 657del5 and Arg215Trp mutations, occurring within the tandem BRCT domains of NBN, although not altering the assembly of the MRE11/RAD50/NBN (MRN) complex, affect the MRE11 IR-induced nuclear foci (IRIF) formation and the DNA doublestrand break (DSB) signaling via the phosphorylation of both ataxia-telangiectasia-mutated (ATM) kinase and ATM downstream targets (e.g., SMC1 and p53). Remarkably, data obtained indicate that the cleavage of the BRCT tandem domains of NBN by the 657del5 mutation affects the DNA damage response less than the Arg215Trp mutation. Indeed, the 70-kDa NBN fragment, arising from the 657del5 mutation, maintains the capability to interact with MRE11 and c-H2AX and to form IRIF. Altogether, the role of the tandem BRCT domains of NBN in the localization of the MRN complex at the DNA DSB and in the activation of the damage response is highlighted.

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Section: Introductionmentioning

confidence: 99%

“…ATM is a serine/threonine kinase which belongs to phosphoinositide 3-kinase (PI3K)-related protein kinase (PIKK) family [6]. ATM plays a pivotal role in cellular and molecular response to DSBs, such as cell cycle checkpoint and DSB repair [6,7]. In G1 checkpoint, ATM transduces DSB signals to Chk2 and p53 by phosphorylation, and induces transient delay of S phase entry at earlier times and more sustained blockage of S phase entry at later times, respectively [8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Mode of ATM-dependent suppression of chromosome translocation

Yamauchi

Suzuki

Oka

et al. 2011

Biochemical and Biophysical Research Communications

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It is well documented that deficiency in ataxia telangiectasia mutated (ATM) protein leads to elevated frequency of chromosome translocation, however, it remains poorly understood how ATM suppresses translocation frequency. In the present study, we addressed the mechanism of ATM-dependent suppression of translocation frequency. To know frequency of translocation events in a whole genome at once, we performed centromere/telomere FISH and scored dicentric chromosomes, because dicentric and translocation occur with equal frequency and by identical mechanism. By centromere/telomere FISH analysis, we confirmed that chemical inhibition orRNAi-mediated knockdown of ATM causes 2~2.5-fold increase in dicentric frequency at first mitosis after 2 Gy of gamma-irradiation in G0/G1. The FISH analysis revealed that ATM/p53-dependent G1 checkpoint suppresses dicentric frequency, since RNAi-mediated knockdown of p53 elevated dicentric frequency by 1.5-fold. We found ATM also suppresses dicentric occurrence independently of its checkpoint role, as ATM inhibitor showed additional effect on dicentric frequency in the context of p53 depletion and Chk1/2 inactivation. Epistasis analysis using chemical inhibitors revealed that ATM kinase functions in the same pathway that requires kinase activity of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to suppress dicentric frequency. From the results in the present study, we conclude that ATM minimizes translocation frequency through its commitment to G1 checkpoint and DNA double-strand break repair pathway that requires kinase activity of DNA-PKcs.

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Ataxia-telangiectasia: from a rare disorder to a paradigm for cell signalling and cancer

Cited by 816 publications

References 114 publications

HMGA proteins promote ATM expression and enhance cancer cell resistance to genotoxic agents

HMGA proteins promote ATM expression and enhance cancer cell resistance to genotoxic agents

Cleavage of the BRCT tandem domains of nibrin by the 657del5 mutation affects the DNA damage response less than the Arg215Trp mutation

Mode of ATM-dependent suppression of chromosome translocation

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