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DNA-damaging agents are able to induce irreversible cell growth arrest and senescence in some types of tumor cells, thus contributing to the static feature of cancer.However, senescent tumor cells may re-enter the cell cycle leading to tumor relapse.Understanding the mechanisms that control the viability of senescent cells may be critical for tumor suppression.Primary human fibroblasts undergoing oncogene-induced or replicative senescence are known to form senescence-associated heterochromatin foci (SAHF), which contribute to the stability of the senescent state.However, it is unclear whether SAHF formation is universal in tumor cells.Moreover, how the SAHF assembly pathway is aetivated in senescent cells is not fully understood.Here we report that the DNA damaging agents doxorubicin (Dox) and 7-Ethyl-10-hydroxycamptothecin (SN-38) were able to induce the formation of SAHF in some tumor cell types, and this induction was accompanied by activation of RB pathway.Contrarily, tumor cells in which the RB pathway could not be activated by Dox or SN-38 failed to form SAHF.In parallel, tumor cells with deficient RB were also unable to form SAHF.In addition, we show that the p38MAPK pathway was involved in tumor cell SAHF formation in response to Dox and SN-38.Furthermore, HBP1, a downstream target of p38MAPK-mediated senescence pathway, was required for SAHF formation.Together, our study highlights the roles of p38MAPK/RB pathway in tumor cell SAHF formation in response to DNA damaging agents, and provides new insights into the mechanisms for DNA damage-mediated tumor suppression.