Tug of War between Survival and Death: Exploring ATM Function in Cancer

Abstract

Ataxia-telangiectasia mutated (ATM) kinase is a one of the main guardian of genome stability and plays a central role in the DNA damage response (DDR). The deregulation of these pathways is strongly linked to cancer initiation and progression as well as to the development of therapeutic approaches. These observations, along with reports that identify ATM loss of function as an event that may promote tumor initiation and progression, point to ATM as a bona fide tumor suppressor. The identification of ATM as a positive modulator of several signalling networks that sustain tumorigenesis, including oxidative stress, hypoxia, receptor tyrosine kinase and AKT serine-threonine kinase activation, raise the question of whether ATM function in cancer may be more complex. This review aims to give a complete overview on the work of several labs that links ATM to the control of the balance between cell survival, proliferation and death in cancer.

ATM has a major role in the double-strand break repair pathway dysregulation in sporadic breast carcinomas and is an independent prognostic marker at both mRNA and protein levels

“…ATM transduces a DSB repair signal to downstream effector machinery by phosphorylating critical protein substrates ( Hu et al , 2010 ). ATM also has a role in cell cycle arrest, apoptosis and senescence, in order to prevent genomic instability ( Stagni et al , 2014 ).…”

Reactive Oxygen Species (ROS)-Activated ATM-Dependent Phosphorylation of Cytoplasmic Substrates Identified by Large-Scale Phosphoproteomics Screen

“…It is not clear at the moment to what extent overlapping sets of substrates are involved in ATM signaling in response to DNA double strand breaks compared with ATM signaling in response to oxidative stress damage response; HMGA1, high mobility group AT-hook 1 protein; UIMCI/RAP80, BRCA1-A complex subunit RAP80 protein; HDGF, Hepatoma-derived growth factor; Ccdc82, Coiled-coil domain-containing protein 82; OSR1, Oxidative Stress Responsive 1 protein kinase; Mre11, Double-strand break repair protein MRE11A (Meiotic recombination 11 homolog 1); Rad50, DNA repair protein RAD50; NBN, Nibrin, Nijmegen breakage syndrome protein 1; MRN, MRE11-RAD50-NBN complex; PEX5, Peroxisomal targeting signal 1 receptor; DNA-PK, DNA-dependent protein kinase, catalytic subunit; SMG1, Serine/threonine-protein kinase SMG1; PP5, Serine/threonine-protein phosphatase 5; PP2A, Protein phosphatase 2A; PP2C, Protein phosphatase 2C; WIP1, Protein phosphatase 1D; Tip60/KAT5, Histone acetyltransferase KAT5; hMOF, Histone acetyltransferase KAT8; KU55933, 2-(4-Morpholinyl)-6-(1-thianthrenyl)-4H-pyran-4-one; U2OS,human osteosarcoma cell line; LKB1,Serine/threonine-protein kinase STK11; AMPK,AMP-activated protein kinase; TSC2,Tuberin; mTORC1, mammalian target of rapamycin complex 1; Akt, Protein kinase B; 4E-BP1, Eukaryotic translation initiation factor 4E-binding protein 1; NEMO,NF-kappa-B essential modulator; TRAF6, TNF receptor-associated factor 6; Hsp27, Heat shock protein beta-1; HIF1a, Hypoxia-inducible factor 1-alpha; VAMP2, Vesicle-associated membrane protein 2; KAP1, Transcription intermediary factor 1-beta; SMC1, Structural maintenance of chromosomes protein 1; H2AX, Histone H2AX; TCEAL3/6, Transcription elongation factor A proteinlike 3; ATE1, Arginyl-tRNA-protein transferase 1; METTL16, Methyltransferase-like protein 16; WNK1, Serine/threonine-protein kinase WNK1; STRING, Search Tool for the Retrieval of Interacting Genes/ Proteins database; EEA1, Early endosome antigen 1; MAPK1/ ERK2, Mitogen-activated protein kinase 1; MAPK3/ERK1, Mitogenactivated protein kinase 3; PRAS40, Proline-rich AKT1 substrate 1; RPTOR, Regulatory-associated protein of mTOR; UREB1, E3 ubiquitin-protein ligase HUWE1; UFD1L, Ubiquitin fusion degradation protein 1 homolog; ATXN3, Ataxin-3; MON1, Vacuolar fusion protein MON1 homolog A; TGF␤, Transforming growth factor beta; PPM1G, Protein phosphatase 1G; NKCC1, Solute carrier family 12 member 2 protein; NKCC2, Na-K-2Cl cotransporter; NCC, sodium-chloride symporter. (31,32). Indeed, a long-standing debate in the A-T field is the relative contributions of DNA double strand breaks and oxidative stress to neurodegeneration and neuronal cell death (33,34).…”

Management of Individuals With a Mutation in the Ataxia Telangiectasia Mutated Gene

“…Knowing if a patient carries a germline ATM mutation may help to guide treatment decisions (Stagni et al, 2014). Those with a germline ATM mutation being treated for ovarian cancer may have a better response to platinum-based therapy or PARP inhibitors, according to a few small retrospective reviews (Gilardini Montani et al, 2013;Pennington et al, 2014).…”