FBXL12 degrades FANCD2 to regulate replication recovery and promote cancer cell survival under conditions of replication stress

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.

Automated summary

This study shows that phosphorylation of FANCD2 by CHK1 triggers its degradation via FBXL12, promoting efficient DNA replication under replication stress. Depletion of FBXL12 leads to trapping of FANCD2 on chromatin, causing replication stress and DNA damage. Upregulation of FBXL12 is associated with reduced survival in patients with CYCLIN E-overexpressing breast tumors.