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CRL4-DCAF8L1 调节 BRCA1 和 BARD1 蛋白稳定性。

CRL4-DCAF8L1 Regulates BRCA1 and BARD1 Protein Stability.

机构信息

Department of Cell Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China.

Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China.

出版信息

Int J Biol Sci. 2022 Jan 24;18(4):1434-1450. doi: 10.7150/ijbs.57178. eCollection 2022.

DOI:10.7150/ijbs.57178
PMID:35280675
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8898372/
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 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.

摘要

BRCA1 在乳腺癌中经常下调，其潜在机制尚不清楚。在这里，我们鉴定了 DCAF8L1，一种 X 连锁基因产物，作为 DDB1-Cullin 相关因子 (DCAF)，用于 CUL4 E3 连接酶靶向 BRCA1 和 BARD1 进行蛋白酶体降解。强制表达 DCAF8L1 导致 BRCA1 和 BARD1 的减少，并损害 DNA 损伤修复功能，导致对辐射和 DNA 损伤剂以及 PARPi 抗癌药物奥拉帕利的敏感性增加；而 DCAF8L1 的耗竭则恢复了 BRCA1 并抑制了其异种移植肿瘤的生长。此外，在人类 H9 ES 细胞从原始状态向幼稚状态转变时，X 染色体重新激活，DCAF8L1 的表达在人类乳腺纤维腺瘤和乳腺癌中被诱导。在人类乳腺纤维腺瘤和乳腺癌中观察到 DCAF8L1 的异常表达。这些发现表明，CRL4 是一种重要的 E3 连接酶，可能参与乳腺癌的发生，可能通过调节 BRCA1 和 BARD1 肿瘤抑制因子的稳定性，将 BRCA1 和 X 染色体失活与乳腺癌发生联系起来。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e3a/8898372/926f31f00134/ijbsv18p1434g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e3a/8898372/3a4a186b6943/ijbsv18p1434g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e3a/8898372/1a92e1c9fa57/ijbsv18p1434g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e3a/8898372/61541c474a0b/ijbsv18p1434g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e3a/8898372/a3b7f11f6ad6/ijbsv18p1434g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e3a/8898372/ccd6bac8855a/ijbsv18p1434g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e3a/8898372/926f31f00134/ijbsv18p1434g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e3a/8898372/3a4a186b6943/ijbsv18p1434g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e3a/8898372/1a92e1c9fa57/ijbsv18p1434g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e3a/8898372/61541c474a0b/ijbsv18p1434g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e3a/8898372/a3b7f11f6ad6/ijbsv18p1434g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e3a/8898372/ccd6bac8855a/ijbsv18p1434g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e3a/8898372/926f31f00134/ijbsv18p1434g006.jpg

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