University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI 96813, USA.
Graduate Program of Molecular Biosciences and Bioengineering, University of Hawaii, Honolulu, HI 96813, USA.
Aging (Albany NY). 2020 Oct 24;12(20):20268-20284. doi: 10.18632/aging.103782.
Emerging Fanconi Anemia (FA) signaling in the field of cancer research annotates the extreme importance of its center player, Fanconi Anemia complementation group D2 (FANCD2) in protecting human cells from going awry. However, a previously-unrecognized form of FANCD2, namely FANCD2-V2, is understudied. We report TRK-Fused Gene (TFG) is critical for roles played by FANCD2-V2 in early responses to DNA damage, but not for FANCD2-V1, the long-known form of FANCD2. FANCD2-V2 forms nuclear foci upon DNA damage, and both its focus appearance and disappearance are earlier than FANCD2-V1. The amino acid/aa 5-100 of TFG and the aa1437-1442 of FANCD2-V2 were identified to contribute to their interaction, which maintains the steady-state level of FANCD2-V2 protein. TFGΔaa5-100 or FANCD2-V2Δaa1437-1442-carrying cells could not show timely focus formation of FANCD2-V2 upon DNA damage and gained carcinogenicity over time. This study provides a previously-unknown key to unlock in-depth insights into maintaining genome stability, fostering translational studies on preventing, diagnosing and/or treating related diseases.
癌症研究领域中新兴的范可尼贫血（FA）信号指出，其核心参与者范可尼贫血互补组 D2（FANCD2）在保护人类细胞免受异常方面的重要性。然而，一种以前未被认识到的 FANCD2 形式，即 FANCD2-V2，研究较少。我们报告 TRK 融合基因（TFG）对于 FANCD2-V2 在 DNA 损伤早期反应中发挥的作用至关重要，但对于 FANCD2-V1 则不重要，FANCD2-V1 是已知的 FANCD2 形式。FANCD2-V2 在 DNA 损伤后形成核焦点，其焦点的出现和消失都早于 FANCD2-V1。TFG 的 aa5-100 和 FANCD2-V2 的 aa1437-1442 被鉴定为相互作用的关键，维持 FANCD2-V2 蛋白的稳定状态。携带 TFGΔaa5-100 或 FANCD2-V2Δaa1437-1442 的细胞不能及时形成 FANCD2-V2 的焦点，随着时间的推移获得致癌性。这项研究提供了一个以前未知的关键，以深入了解维持基因组稳定性，促进预防、诊断和/或治疗相关疾病的转化研究。
