CRL4-DCAF8L1 Regulates BRCA1 and BARD1 Protein Stability.
CRL4-DCAF8L1 Regulates BRCA1 and BARD1 Protein Stability.
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CRL4-DCAF8L1 调节 BRCA1 和 BARD1 蛋白质稳定性
DOI：
10.7150/ijbs.57178
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发表时间：
2022
影响因子：
9.2
通讯作者：
Shao G
中科院分区：
文献类型：
--
作者：
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
BRCA1在乳腺癌中经常下调，其潜在机制尚不清楚。在这里，我们确定了DCAF8L1，一个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。DCAF8L1的强制表达导致BRCA1和BARD1的减少，DNA损伤修复功能受损，对辐射和DNA损伤剂以及PARPi抗癌药物奥拉帕尼（Olaparib）的敏感性增加；而DCAF8L1的缺失恢复了BRCA1并抑制了其异种移植肿瘤的生长。此外，当Xi染色体被重新激活时，DCAF8L1在人H9 ES细胞从primed状态过渡到naïve状态时被诱导表达。DCAF8L1在乳腺纤维腺瘤和乳腺癌中均有异常表达。这些发现提示CRL4DCAF8L1是一种重要的E3连接酶，可能通过调节BRCA1和BARD1抑癌基因的稳定性参与乳腺癌的发展，将BRCA1和X染色体失活与乳腺癌的发生联系起来。
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 CRL4DCAF8L1 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.
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影响因子：
78.5
作者：
Pageau, Gayle J.;Hall, Lisa L.;Lawrence, Jeanne B.
通讯作者：
Lawrence, Jeanne B.
DOI：
10.1073/pnas.0503793102
发表时间：
2005-06-28
影响因子：
11.1
作者：
Furuta, S;Jiang, XZ;Lee, WH
通讯作者：
Lee, WH
影响因子：
4.3
作者：
Helleday, T;Bryant, HE;Schultz, N
通讯作者：
Schultz, N
DOI：
10.1073/pnas.0711613105
发表时间：
2008-02-05
影响因子：
11.1
作者：
Liu, Suling;Ginestier, Christophe;Wicha, Max S.
通讯作者：
Wicha, Max S.
影响因子：
13.8
作者：
Jackson, Sarah;Xiong, Yue
通讯作者：
Xiong, Yue