Circular RNAs (circRNAs) are a new class of noncoding RNAs, play a crucial role in tumor initiation and development. Hsa_circ_0001546 is a novel circular RNA that was downregulated in gastric cancer (GC) tissues, however its function and mechanism in GC has not been studied. Our study verified that circ_0001546 was decreased in GC and correlated with the poor prognosis. Next, Pull-down assay and dual-luciferase reporter assay verified that miR-421 was a target of circ_0001546 while ATM (Ataxia telangiectasia mutated) was target by miR-421. Overexpression of circ_0001546 inhibited the proliferation and chemoresistance of HGC-27 cells, and increased the expression of ATM. In addition, circ_0001546 overexpression reversed the effect of miR-421 overexpression. What is more, circ_0001546 inhibits the chemoresistance of HGC-27 cells to L-OPH (Oxaliplatin) may through the activation of the ATM/checkpoint kinase 2 (Chk2)/p53-dependent signaling pathway. In summary, our study proved that circ_0001546 sponges miR-421 to upregulate the expression level of ATM and inhibit the proliferation and chemoresistance through the activation of the ATM/Chk2/p53-dependent pathway. (C) 2019 Elsevier Inc. All rights reserved.