Molecular mechanisms through which RNF8 promotes tumor progression and chemoresistance. In non-cancerous cells (A), RNF8 positively regulates the DNA damage response. In contrast, overexpressed RNF8 in cancerous cells directly promotes the nuclear localization and protein stability of TWIST via K63-linked ubiquitination. In breast cancer patients (B), high expression of RNF8 correlates with tumor progression, conferring chemoresistance and promoting cancer metastasis. Ub, ubiquitination.