## 2 Materials and Methods
### Neuroblastoma Cell Culture and Treatments  
Parental SH-SY5Y human neuroblastoma cell line was cultured in high glucose DMEM (Thermo Fisher Scientific, Waltham, MA, USA, 21969-035) supplemented with 10% FCS (Thermo Fisher Scientific, Waltham, MA, USA, A3160802), 1% L-Glutamine (Thermo Fisher Scientific, Waltham, MA, USA, 25030-024) and 0.1% Penicillin/Streptomycin (Thermo Fisher Scientific, Waltham, MA, USA, 15140-122). _ATM_ knockdown SH-SYSY cells were kept in a selection medium, as explained later. Stable knockdown of _ATM_ in SH-SYSY was achieved via lentiviral transduction of five different MISISON short hairpin RNAs targeting _ATM_ (shRNA, commercially available at Sigma-Aldrich, St. Louis, MO, USA) and one non-targeting control shRNA, targeting no known mammalian genes (Sigma-Aldrich, St. Louis, MO, USA, SHC002, hereafter referred to as NT CTRL, gift from Prof. Dr. [PERSON]) in mammalian expression vector pLKO.1. The shATM sequences were:  
sh_ATM_#1-5 CCGGCCAAGGTCATATGATACTTACCTGAGCAATACATCAGACCTTGTTTTTG-3 (cat.no. TRCN0000194861),  
sh_ATM_#2-5 CCGGTGTGTGCAAAATCTCAATCCGAATTTGATGAAGTTTTGACCATTTTG-3 (cat.no. TRCN0000245108),  
sh_ATM_#3-5 CCGGTGATGGTCTTAAGGAAACATCTCCGAGAGATTCCTTAAGACCATATTTTG-3 (cat.no. TRCN000010299),  
sh_ATM_#4-5 CCGGCCTTTCATCAGCCCTTTAGACCTGAGTTCTAAAAGGCTGAAATGATTTTG-3 (cat.no. TRCN000039948),  
sh_ATM_#5-5 CCGGCCTCCCAATTCTCACAGTAACTCGAGTACTGTGAAGAATTGAGGCTTTTG-3 (cat.no. TRCN000039951). Stable KD cells were generated by transfecting 2 ug of the respective shRNA or NT CTRL plasmid DNA, 1.5 ug gag/pol plasmid DNA (psPAX2, Addgene #12260) and 0.5 ug VSV-G envelope plasmid DNA (pMD2.G, Addgene #12259) into HEK293T cells using FuGENE HD transfection reagent (Promega, Fitchburg, WI, USA, E2311) following the manufacturer's instructions. psPAX2 was a gift from [PERSON] (Addgene plasmid # 12260; [[http://n2t.net/addgene:12260](http://n2t.net/addgene:12260)]([http://n2t.net/addgene:12260](http://n2t.net/addgene:12260)), accessed on 1 October 2023; RRID:Addgene_12260). pMD2.G was a gift from [PERSON] (Addgene plasmid # 12259; [[http://n2t.net/addgene:12259](http://n2t.net/addgene:12259)]([http://n2t.net/addgene:12259](http://n2t.net/addgene:12259)), accessed on 1 October 2023; RRID:Addgene_12259). After 16 h and 40 h posttransfection, the viral supernatant was collected, pooled, sterile-filtered (0.45 um) and applied to the SH-SY5Y cells in a 1:1 mixture with fresh medium supplemented with 3 ug/mL polybyrene (Sigma-Aldrich, St. Louis, MO, USA, TR-1003). SH-SYSY cells were transduced for 24 h and selected via bulk selection using puromycin (Santa Cruz Biotechnology, Dallas, TX, USA, sc-108071). To achieve this, the SH-SY5Y culture medium was supplemented with 1.25 ug/mL puromycin as determined by the kill curve in parental cells. Cells were generally maintained in puromycin selection medium in order to reduce the probability of KD loss. After expansion, sh_ATM_-containing cells were assessed for protein and RNA levels, and sh_ATM_#2 was selected for further experiments after achieving the best KD. For stress experiments, parental and knockdown cells were treated with chloroquine (CQ, Sigma-Aldrich, St. Louis, MO, USA, C6628) for osmotic stress, bleomycin (BLEO, Merck Millipore, Burlington, MA, USA, 203408-250 MG) for genotoxic stress, sodium arsenite (NaARS, Sigma-Aldrich, St. Louis, MO, USA, S7400-100G) for oxidative stress, and LY-294002 (LY, Cayman Chemical Company, Ann Arbor, MI, USA, 70920) for trophic stress via phosphoinositide 3-kinase (PI3K) inhibition. An amount of 20 um chloroquine was administered for 24 h with sterile water as a control. BLEUO treatment was at 5 um for 8 h, with DMSO as the control condition. NaARS was delivered at 0.5 mM for 45 min, water serving as a control. LY was administered at a concentration of 10 ug/mL for 24 h, with DMSO as a control. For pre-treatment of parental SH-SY5Y cells with the ATM inhibitor KU-55933 (KU, Selleckchem, Houston, TX, USA, S1092), 10 \(\upmu\)M were used over 30 min, prior to the cell stress exposure, with DMSO as a control.