在复制应激的响应中，Fanconi贫血（FA）信号传导是一个关键的基因组维护途径。本文报道了通过CHK1对关键途径蛋白FANCD2的磷酸化，触发其依赖于FBXL12的蛋白酶体降解，从而促进FANCD2在阻滞的复制叉中的清除。这有助于在CYCLIN E诱导和药物诱导的复制应激条件下进行高效的DNA复制。通过对具有激酶降解蛋白突变体的FANCD2缺陷成纤维细胞进行重构未能恢复叉进展。在缺乏FBXL12的情况下，FANCD2陷入染色质中，导致复制应激和过度的DNA损伤。在人类癌症中，FBXL12、CYCLIN E和FA信号传导呈正相关，并且FBXL12的上调与高表达CYCLIN E的乳腺肿瘤患者生存率降低相关。最后，FBXL12的耗竭加剧了致癌基因诱导的复制应激，并使癌细胞对WEE1抑制引起的药物诱导的复制应激更敏感。总的来说，我们的结果表明在CYCLIN E过表达的癌症中，FBXL12构成了一个易感因子和潜在的治疗靶点。版权所有 © 2023年作者。由Elsevier Inc.出版，保留所有权利。

Fanconi anemia (FA) signaling, a key genomic maintenance pathway, is activated in response to replication stress. Here, we report that phosphorylation of the pivotal pathway protein FANCD2 by CHK1 triggers its FBXL12-dependent proteasomal degradation, facilitating FANCD2 clearance at stalled replication forks. This promotes efficient DNA replication under conditions of CYCLIN E- and drug-induced replication stress. Reconstituting FANCD2-deficient fibroblasts with phosphodegron mutants failed to re-establish fork progression. In the absence of FBXL12, FANCD2 becomes trapped on chromatin, leading to replication stress and excessive DNA damage. In human cancers, FBXL12, CYCLIN E, and FA signaling are positively correlated, and FBXL12 upregulation is linked to reduced survival in patients with high CYCLIN E-expressing breast tumors. Finally, depletion of FBXL12 exacerbated oncogene-induced replication stress and sensitized cancer cells to drug-induced replication stress by WEE1 inhibition. Collectively, our results indicate that FBXL12 constitutes a vulnerability and a potential therapeutic target in CYCLIN E-overexpressing cancers.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.