Crotonylation of MCM6 enhances chemotherapeutics sensitivity of breast cancer via inducing DNA replication stress

Abstract Breast cancer is associated with high morbidity and mortality, which are closely influenced by protein post‐translational modifications (PTMs). Lysine crotonylation (Kcr) serves as a newly identified PTM type that plays a role in various biological processes; however, its involvement in breast cancer progression remains unclear. Minichromosome maintenance 6 (MCM6) is a critical component of DNA replication and has been previous confirmed to exhibit a significant role in tumorigenesis. Despite this, a comprehensive analysis of MCM6, particularly regarding its modifications in breast cancer is lacking. In this study, we found MCM6 is upregulated in breast invasive carcinoma (BRCA) and is associated with poorer overall survival by regulating the DNA damage repair mechanisms. Furthermore, MCM6‐knockdown resulted in decreased cell proliferation and inhibited the DNA replication, leading to DNA replication stress and sustained DNA damage, thereby enhancing the chemotherapeutic sensitivity of breast cancer. Additionally, SIRT7‐mediated crotonylation of MCM6 at K599 (MCM6‐K599cr) was significantly upregulated in response to DNA replication stress, primarily due to the disassemebly of the MCM2‐7 complex and regulated by RNF8‐mediated ubiquitination. Concurrently, kaempferol, which acts as a regulator of SIRT7, was found to enhance the Kcr level of MCM6, reducing tumour weight, particular when combined with paclitaxel, highlighting its potential chemotherapeutic target for BRCA therapy.