MDC1 promotes nuclear localization of Beclin-1 and supports its role in ATM pathway in response to oxidative stress

Cancer cells undergo various adaptive measures to survive the high level of oxidative stress that threatens genomic integrity and survival. This oxidative stress is enhanced during Cancer chemotherapy and undermines the drug efficacy due to the altered cellular signalling, which promotes cell survival and Cancer progression. While oxidative stress induces Autophagy, the ensuing genotoxic stress activates the DNA damage response (DDR) in Cancer cells. Cancer cells show high dependency on these mechanisms for survival, which also indicates the likelihood of increased cooperativity between them under stress. In this study, through co-immunoprecipitation and immunofluorescence assays, we have demonstrated strong interaction between MDC1 and Beclin-1 in H₂O₂ and doxorubicin treated HeLa cells. Furthermore, we observed that in Hela cells depleted of MDC1, the translocation of Beclin-1 to the nucleus was abrogated, which adversely affected both the DDR and Autophagy response in these cells. Additionally, we have analyzed the effect of Chk2 kinase activity on this interaction, and the presence of phospho-CHK2 probably supports the nuclear activity of Beclin-1 through its phosphorylation, but is dispensable for the nuclear translocation of Beclin-1. In conclusion, our findings contribute to the understanding of the crosstalk between DDR and Autophagy for cell survival under genotoxic stress, with potential implications on the efficacy of drug treatment.

Autophagy; Cancer; Cellular stress and MDC1; DNA damage response.