Poly(ADP‑ribose) polymerase 1/2 inhibitors decrease the ubiquitination of ALC1 mediated by CHFR in breast cancer

Wang,Yiran; Wang,Ying; Wang,Ning; You,Lifang; Long,Fei; Shao,Changjuan; Wang,Yajie; Wu,Jiaxue

doi:10.3892/or.2019.7242

Poly(ADP‑ribose) polymerase 1/2 inhibitors decrease the ubiquitination of ALC1 mediated by CHFR in breast cancer

Authors:
- Yiran Wang
- Ying Wang
- Ning Wang
- Lifang You
- Fei Long
- Changjuan Shao
- Yajie Wang
- Jiaxue Wu
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Affiliations: Department of Oncology, Changhai Hospital, Second Military Medical University, Shanghai 200433, P.R. China, School of Life Sciences, Fudan University, Shanghai 200438, P.R. China, Zhongshan Hospital and School of Life Sciences, Fudan University, Shanghai 200032, P.R. China
Published online on: July 18, 2019 https://doi.org/10.3892/or.2019.7242
Pages: 1467-1474

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Abstract

With the increasing use of poly(ADP‑ribose) polymerase (PARP) inhibitors in cancer therapy, understanding their resistance is an urgent research quest. Additionally, CHFR is an E3 ubiquitin ligase, recruited to double‑strand breaks (DSBs) by PAR. Furthermore, ALC1 is a new oncogene involved in the invasion and metastasis of breast cancer. Moreover, PARylated PARP1 activates ALC1 at sites of DNA damage, yet the underlying mechanism remains unclear. Mass spectrometric analysis, western blot analysis and immunoprecipitation were performed to confirm the interaction between CHFR and ALC1 in the physiological condition. Deletion mutants of CHFR and ALC1 were generated to map the interaction domain. PARP1/2 inhibitors were added to identify the ubiquitination of ALC1 by CHFR. ALC1 half‑life was examined to compare the expression of ALC1 protein in the presence and absence of PARP1/2 inhibitors. The results revealed that the transcriptional level of ALC1 was not upregulated in breast cancer tissues. CHFR interacted with ALC1. The PBZ domain of CHFR, the PMD domain and the MACRO domain of ALC1 domain are the necessary regions for the interaction depending on PAR. Ubiquitination of ALC1 by CHFR was dependent on PARylation and resulted in the degradation of PARylated ALC1. PARP1/2 inhibitors decreased the ubiquitination of PAR‑dependent ALC1, and the expression of ALC1 was upregulated by PARP1/2 inhibitors. Ubiquitination mediated by CHFR resulted in the degradation of ALC1. In conclusion, PARP1/2 inhibitors decrease the ubiquitination of ALC1 leading to the accumulation of ALC1, which affects the therapeutic effects of DNA damage response drugs in breast cancer treatment.

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