Poly(ADP-ribose) polymerase 1 (PARP1), a critical DNA repair protein, is frequently upregulated in breast tumors with a key role in breast cancer progression. Consequently, PARP inhibitors have emerged as promising therapeutics for breast cancers with DNA repair deficiencies. However, relatively little is known about the regulatory mechanism of PARP1 expression and the determinants of PARP 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 PARP1 through its carboxy-terminal region containing the transmembrane domain, and targets PARP1 for ubiquitination and subsequent proteasomal degradation. Moreover, induced expression of RNF144A decreases PARP1 protein levels and renders breast cancer cells resistant to the clinical-grade PARP inhibitor olaparib. Conversely, knockdown of endogenous RNF144A increases PARP1 protein levels and enhances cellular sensitivity to olaparib. Together, these findings define RNF144A as a novel regulator of PARP1 protein abundance and a potential determinant of PARP inhibitor sensitivity in breast cancer cells, which may eventually guide the optimal use of PARP inhibitors in the clinic.
[1]Fudan Univ, Shanghai Med Coll, Shanghai Canc Ctr, Shanghai 200032, Peoples R China.
[2]Fudan Univ, Shanghai Med Coll, Inst Biomed Sci, Shanghai 200032, Peoples R China.
[3]Fudan Univ, Shanghai Med Coll, Shanghai Canc Ctr, Dept Oncol, Shanghai 200032, Peoples R China.
[4]Fudan Univ, Shanghai Med Coll, Shanghai Canc Ctr, Canc Inst, Shanghai 200032, Peoples R China.
[5]Fudan Univ, Shanghai Med Coll, Shanghai Canc Ctr, Dept Breast Surg, Shanghai 200032, Peoples R China.
[6]Fudan Univ, Shanghai Med Coll, Key Lab Breast Canc Shanghai, Shanghai 200032, Peoples R China.
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