RBR-type E3 ubiquitin ligase RNF144A targets PARP1 for ubiquitin-dependent degradation and regulates PARP inhibitor sensitivity in breast cancer cells.

Poly(ADP-ribose) polymerase 1 a critical DNA repair protein, is frequently upregulated in breast tumors with a key role in breast cancer progression. Consequently, inhibitors have emerged as promising therapeutics for breast cancers with DNA repair deficiencies. However, relatively little is known about the regulatory mechanism of expression and the determinants of Pduanyu37 inhibitor sensitivity in breast cancer cells. Here, we report that ring finger protein 144A (RNF144A), a RING-between-RING (RBR)-type E3 ubiquitin ligase with an unexplored functional role in human cancers, interacts with Pduanyu371 through its carboxy-terminal region containing the transmembrane domain, and targets Pduanyu371 for ubiquitination and subsequent proteasomal degradation. Moreover, induced expression of RNF144A decreases Pduanyu371 protein levels and renders breast cancer cells resistant to the clinical-grade Pduanyu37 inhibitor olaparib. Conversely, knockdown of endogenous RNF144A increases Pduanyu371 protein levels and enhances cellular sensitivity to olaparib. Together, these findings define RNF144A as a novel regulator of Pduanyu371 protein abundance and a potential determinant of Pduanyu37 inhibitor sensitivity in breast cancer cells, which may eventually guide the optimal use of Pduanyu37 inhibitors in the clinic.

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