p53-deficient cancer cells hyperactivate DNA double-strand break repair pathways to overcome chemotherapeutic damage and augment survival.

backgroundp53 deficiency in cancer is associated with chemoresistance and cancer progression. However, the precise role of p53 in regulating DDR in the context of chemoresistance is still unclear. METHODS AND

resultsIn the present study, we investigated the regulatory role of p53 on the cellular recovery potential upon transient DNA damage. p53 deficiency promotes cell survival following transient DNA damage induction. During recovery, p53 deficient cells display temporary S/G2/M arrest, returning to normal cell cycle profile, while p53 proficient cells remain permanently arrested in the S-phase. Additionally, colony formation assay revealed 50% clonogenicity in p53-proficient cells, while p53-deficient cells showed 90% clonogenicity. Chemoresistance also correlated with accelerated DNA repair in p53-deficient cells. Since doxorubicin induces DNA double-strand breaks, whose repair is driven by two major pathways: homology-directed repair and nonhomologous end joining, we measured their activity during the recovery period. During the early recovery period, both pathways were activated irrespective of p53 expression status. However, during the late recovery time point, NHEJ and HDR activities returned to basal in p53-deficient cells, while their activity was significantly reduced in p53-proficient cells. NHEJ inhibitor Ku57788 could overcome the chemoresistance in p53-deficient cells.

conclusionThus, our findings suggest that sustained DDR promotes chemoresistance and enhanced survival in p53-deficient cancer cells.