Abstract 1739: Deciphering the molecular links between DNA damage response and autophagy in cancer: Implications for chemotherapy resistance

Abstract DNA damage response (DDR) guards the cells against DNA damage through coordinated detection and repair of DNA lesions. However, cancer cells rewire this mechanism to mitigate genotoxic insults induced by chemotherapy, thereby attenuating treatment efficacy. This adaptive DDR represents a critical barrier to effective cancer treatment, necessitating elucidation of molecular determinants conferring chemoresistance. Concomitantly, autophagy is activated as a cytoprotective mechanism under genotoxic stress, and emerging evidence suggests functional crosstalk between DDR and autophagy pathways in orchestrating cellular survival. Mediator of DNA damage checkpoint 1 (MDC1) is an indispensable anchor protein of double strand break repair, while Beclin-1 is canonically characterized as a cytoplasmic autophagy regulator. However, their functional convergence during genotoxic stress remains unexplored. We utilized a comprehensive approach combining computational modeling (molecular docking) with cellular assays, including co-immunoprecipitation (Co-IP), immunofluorescence microscopy, and immunoblotting in HeLa cell models with differential MDC1 expression. Here, we report an interaction between MDC1 and Beclin-1 that is dynamically enhanced following genotoxic insult. Remarkably, we demonstrate that genotoxic agents induce nuclear translocation of Beclin-1, a process that is MDC1-dependent. Further, we also show that nuclear Beclin-1 supports the accumulation and retention of various DDR effectors and hence promotes DNA repair. Additionally, we have analyzed the effect of CHK2 kinase activity on this interaction and 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. We believe that the cancer cells rely on this crosstalk to evade chemotherapy induced cytotoxicity. Given that the cytotoxic efficacy of most chemotherapeutic agents relies on inducing irreparable DNA damage, the MDC1-Beclin-1 axis may constitute a pivotal cytoprotective mechanism exploited by malignant cells to enhance DNA repair capacity and thereby circumvent therapeutic intervention. These findings establish a compelling rationale for pharmacological disruption of the MDC1-Beclin-1 interaction as a strategy to resensitize refractory tumors to DNA-damaging chemotherapy. This work offers mechanistic insights for developing next-generation combination therapies targeting the DDR-autophagy interface to surmount treatment resistance. Citation Format: Kavya Ajit Pandya, Neeru Singh. Deciphering the molecular links between DNA damage response and autophagy in cancer: Implications for chemotherapy resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1739.