Hu Wen-Feng, Krieger Kimiko L, Lagundžin Dragana, Li Xueli, Cheung Ronald S, Taniguchi Toshiyasu, Johnson Keith R, Bessho Tadayoshi, Monteiro Alvaro N A, Woods Nicholas T
1Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198 USA.
2Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China.
Cell Death Discov. 2019 Jun 19;5:105. doi: 10.1038/s41420-019-0185-3. eCollection 2019.
BRCA1 C-terminal domains are found in a specialized group of 23 proteins that function in the DNA damage response to protect genomic integrity. C-terminal domain phosphatase 1 (CTDP1) is the only phosphatase with a BRCA1 C-terminal domain in the human proteome, yet direct participation in the DNA damage response has not been reported. Examination of the CTDP1 BRCA1 C-terminal domain-specific protein interaction network revealed 103 high confidence interactions enriched in DNA damage response proteins, including FANCA and FANCI that are central to the Fanconi anemia DNA repair pathway necessary for the resolution of DNA interstrand crosslink damage. CTDP1 expression promotes DNA damage-induced FANCA and FANCD2 foci formation and enhances homologous recombination repair efficiency. CTDP1 was found to regulate multiple aspects of FANCI activity, including chromatin localization, interaction with γ-H2AX, and SQ motif phosphorylations. Knockdown of CTDP1 increases MCF-10A sensitivity to DNA interstrand crosslinks and double-strand breaks, but not ultraviolet radiation. In addition, CTDP1 knockdown impairs in vitro and in vivo growth of breast cancer cell lines. These results elucidate the molecular functions of CTDP1 in Fanconi anemia interstrand crosslink repair and identify this protein as a potential target for breast cancer therapy.
BRCA1羧基末端结构域存在于一组特殊的23种蛋白质中，这些蛋白质在DNA损伤反应中发挥作用以保护基因组完整性。羧基末端结构域磷酸酶1（CTDP1）是人类蛋白质组中唯一具有BRCA1羧基末端结构域的磷酸酶，但尚未有其直接参与DNA损伤反应的报道。对CTDP1的BRCA1羧基末端结构域特异性蛋白质相互作用网络的研究揭示了103种高度可信的相互作用，这些相互作用在DNA损伤反应蛋白中富集，包括范可尼贫血DNA修复途径核心的FANCA和FANCI，该途径对于解决DNA链间交联损伤是必需的。CTDP1的表达促进DNA损伤诱导的FANCA和FANCD2灶形成，并提高同源重组修复效率。研究发现CTDP1可调节FANCI活性的多个方面，包括染色质定位、与γ-H2AX的相互作用以及SQ基序磷酸化。敲低CTDP1会增加MCF-10A对DNA链间交联和双链断裂的敏感性，但不会增加对紫外线辐射的敏感性。此外，敲低CTDP1会损害乳腺癌细胞系的体外和体内生长。这些结果阐明了CTDP1在范可尼贫血链间交联修复中的分子功能，并确定该蛋白为乳腺癌治疗的潜在靶点。
