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.

在一组特殊的23种蛋白质中发现了BRCA1 C末端结构域，这些蛋白质在DNA损伤反应中起着保护基因组完整性的作用。C-末端结构域磷酸酶1（CTDP1）是人类蛋白质组中唯一具有BRCA1 C-末端结构域的磷酸酶，但尚无直接参与DNA损伤反应的报道。CTDP1 BRCA1 C末端域特异性蛋白质相互作用网络的检查显示103高可信度相互作用富含DNA损伤反应蛋白，包括FANCA和FANCI，这是解决DNA间链交联损伤所必需的Fanconi贫血DNA修复途径的核心。CTDP1表达促进DNA损伤诱导的FANCA和FANCD2灶形成，并增强同源重组修复效率。发现CTDP1可以调节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可以提高MCF-10A对DNA链间交联和双链断裂的敏感性，但不增强对紫外线的敏感性。另外，CTDP1敲低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，并将该蛋白鉴定为乳腺癌治疗的潜在靶标。