MPP8 Facilitates DNA DSB Repair via NHEJ to Promote Chemoresistance of TNBC Independent of Methyl‐H3K9 Binding

ABSTRACT While cytotoxic chemotherapy remains the backbone of systemic treatments for triple‐negative breast cancer (TNBC), patients frequently develop resistance and recurrence, leading to poor clinical outcomes. However, molecular mechanisms underlying chemotherapy resistance are enigmatic. In this study, a pivotal epigenetic regulator MPP8 is characterized as a key player in TNBC chemoresistance. MPP8 depletion in TNBC cells significantly increases levels of cleaved‐ PARP1 and Caspase3 and reduces clonogenic survival upon doxorubicin or IR treatment, which are accompanied by a drastically delayed DNA damage repair progression and γH2AX clearance. Mechanistically, MPP8 robustly interacts with DNAPK complex and promotes DNA double‐strand break (DSB) repair via non‐homologous end joining (NHEJ) pathway independent of its epigenetic functions. Upon DNA damage, MPP8 is dynamically recruited to DNA DSBs, where it facilitates the recruitment of ligase complex and assembly of NHEJ apparatus to expedite DNA repair progression. Correspondingly, MPP8 knockdown resensitizes TNBC to doxorubicin treatment in murine orthotopic xenograft models. Together, these findings not only highlight a crucial non‐canonical function of MPP8 in DSB repair as a novel NHEJ accessary factor but also suggest a potential strategy to improve efficacy and outcomes of standard TNBC chemotherapy based on MPP8 expression levels.