WDR61 ablation triggers R-loop accumulation and suppresses breast cancer progression.

ABSTRACT

Although, superkiller complex protein 8 (SKI8), previously known as WDR61 has been identified and mapped in breast tumor, little is currently known about its function. This study aims to elucidate the role of WDR61 in breast tumor development and its potential as a therapeutic target. Here, we show that tamoxifen-induced knockout of Wdr61 reduces the risk of breast tumors, resulting in smaller tumor size and weight, and improved overall survival. Furthermore, we show that knockdown of WDR61 compromises the proliferation of breast tumor cells with reduced colony-forming capacity. Further investigations demonstrate that the protective effect of WDR61 loss on breast tumor development is due to genomic instability. Mechanistic studies reveal that WDR61 interacts with the R-loop, and loss of WDR61 leads to R-loops accumulation in breast tumor cells, causing DNA damage and subsequent inhibition of cell proliferation. In summary, this study highlights the critical dependence of breast tumors on WDR61, which suppresses R-loop and counteracts endogenous DNA damage in tumor cells.