In humans, the release factor eRF3a exists in several forms that differ in the length of the polyglycine tract (7, 10, 11 or 12 glycines) in its N-terminal domain. For the 12-Gly eRF3a, an association with cancer risk and a decreased affinity for the cytoplasmic poly (A) binding protein have already been established. In this work, HCT116 colon cancer cells were treated with low doses of doxorubicin, which is known to induce senescence in these cells with high efficiency. The expression of p21 and p53 (senescence marker proteins) as well as lysosomal β-galactosidase activity were reduced when 12-Gly-eRF3a was overexpressed or eRF3a was depleted in cells. If low activity of mTORC1 pathway might be responsible for reduced senescence onset after eRF3a depletion, its activity is maintained in cells overexpressing 12-Gly-eRF3a. In both cases, a defect in termination efficiency could be involved.