CRL4-DCAF8L1 Regulates BRCA1 and BARD1 Protein Stability

Liu, Fei; Han, Qianying; Zhang, Ting; Chang, Fen; Deng, Jingcheng; Huang, Xiaotian; Wang, Weiping; Xu, Yongjie; Li, Qin; Xu, Luzheng; Zhang, Bo; Li, Wentong; Li, Li; Su, Yanrong; Li, Yang; Shao, Genze

doi:10.7150/ijbs.57178

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Int J Biol Sci 2022; 18(4):1434-1450. doi:10.7150/ijbs.57178 This issue Cite

Research Paper

CRL4-DCAF8L1 Regulates BRCA1 and BARD1 Protein Stability

Fei Liu^1,2,#, Qianying Han^1,#, Ting Zhang¹, Fen Chang¹, Jingcheng Deng¹, Xiaotian Huang¹, Weiping Wang³, Yongjie Xu¹, Qin Li¹, Luzheng Xu⁴, Bo Zhang², Wentong Li⁵, Li Li¹, Yanrong Su⁶, Yang Li¹, Genze Shao^1✉

1. Department of Cell Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China
2. Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China
3. Department of Biochemsitry; School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China
4. Medical and Health Analysis Center, Peking University, Beijing, 100191, China
5. Department of Pathology, Weifang Medical University, Shandong, 261041, China
6. The Irma H. Russo, MD Breast Cancer Research Laboratory, Fox Chase Cancer Center-Temple University Health System, Philadelphia, PA, 19111, USA
# These authors contribute equally to the article

Citation:

Liu F, Han Q, Zhang T, Chang F, Deng J, Huang X, Wang W, Xu Y, Li Q, Xu L, Zhang B, Li W, Li L, Su Y, Li Y, Shao G. CRL4-DCAF8L1 Regulates BRCA1 and BARD1 Protein Stability. Int J Biol Sci 2022; 18(4):1434-1450. doi:10.7150/ijbs.57178. https://www.ijbs.com/v18p1434.htm

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Abstract

BRCA1 is frequently down-regulated in breast cancer, the underlying mechanism is unclear. Here we identified DCAF8L1, an X-linked gene product, as a DDB1-Cullin associated Factor (DCAF) for CUL4 E3 ligases to target BRCA1 and BARD1 for proteasomal degradation. Forced expression of DCAF8L1 caused reduction of BRCA1 and BARD1, and impaired DNA damage repair function, conferring increased sensitivity to irradiation and DNA damaging agents, as well as Olaparib, a PARPi anticancer drug; while depletion of DCAF8L1 restored BRCA1 and suppressed the growth of its xenograft tumors. Furthermore, the expression of DCAF8L1 was induced in human H9 ES cells during transition from primed to naïve state when Xi chromosome was reactivated. Aberrant expression of DCAF8L1 was observed in human breast fibroadenoma and breast cancer. These findings suggest that CRL4^DCAF8L1 is an important E3 ligase that may participate in the development of breast cancer, probably through regulating the stability of BRCA1 and BARD1 tumor suppressor, linking BRCA1 and X chromosome inactivation to breast carcinogenesis.

Keywords: BRCA1, BARD1, DCAF8L1, ubiquitination, breast cancer, X chromosome inactivation

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APA

Liu, F., Han, Q., Zhang, T., Chang, F., Deng, J., Huang, X., Wang, W., Xu, Y., Li, Q., Xu, L., Zhang, B., Li, W., Li, L., Su, Y., Li, Y., Shao, G. (2022). CRL4-DCAF8L1 Regulates BRCA1 and BARD1 Protein Stability. International Journal of Biological Sciences, 18(4), 1434-1450. https://doi.org/10.7150/ijbs.57178.

ACS

Liu, F.; Han, Q.; Zhang, T.; Chang, F.; Deng, J.; Huang, X.; Wang, W.; Xu, Y.; Li, Q.; Xu, L.; Zhang, B.; Li, W.; Li, L.; Su, Y.; Li, Y.; Shao, G. CRL4-DCAF8L1 Regulates BRCA1 and BARD1 Protein Stability. Int. J. Biol. Sci. 2022, 18 (4), 1434-1450. DOI: 10.7150/ijbs.57178.

NLM

CSE

Liu F, Han Q, Zhang T, Chang F, Deng J, Huang X, Wang W, Xu Y, Li Q, Xu L, Zhang B, Li W, Li L, Su Y, Li Y, Shao G. 2022. CRL4-DCAF8L1 Regulates BRCA1 and BARD1 Protein Stability. Int J Biol Sci. 18(4):1434-1450.

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