2. Academic Validation
  3. FBXL12 degrades FANCD2 to regulate replication recovery and promote cancer cell survival under conditions of replication stress

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

  • Mol Cell. 2023 Aug 9;S1097-2765(23)00599-3. doi: 10.1016/j.molcel.2023.07.026.
Andrä Brunner 1,  Qiuzhen Li 2,  Samuele Fisicaro 2,  Alexandros Kourtesakis 2,  Johanna Viiliäinen 2,  Henrik J Johansson 3,  Vijaya Pandey 4,  Adarsh K Mayank 4,  Janne Lehtiö 3,  James A Wohlschlegel 4,  Charles Spruck 5,  Juha K Rantala 6,  Lukas M Orre 3,  Olle Sangfelt 7
Affiliations

Affiliations

  • 1 Department of Cell and Molecular Biology, Karolinska Institutet, Solna 17165, Stockholms län, Sweden. Electronic address: andra.brunner@ki.se.
  • 2 Department of Cell and Molecular Biology, Karolinska Institutet, Solna 17165, Stockholms län, Sweden.
  • 3 Department of Oncology and Pathology, Karolinska Institutet, Science for Life Laboratory, Solna 17165, Stockholms län, Sweden.
  • 4 Department of Biological Chemistry, University of California, Los Angeles, Los Angeles 90095, CA, USA.
  • 5 NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla 92037, CA, USA.
  • 6 Department of Oncology and Metabolism, University of Sheffield, Sheffield S10 2RX, South Yorkshire, UK; Misvik Biology, Turku 20520, Finland.
  • 7 Department of Cell and Molecular Biology, Karolinska Institutet, Solna 17165, Stockholms län, Sweden. Electronic address: olle.sangfelt@ki.se.
PMID: 37591242 DOI: 10.1016/j.molcel.2023.07.026
Abstract

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.

Keywords

CYCLIN E; DNA damage; FANCD2; FBXL12; Fanconi anemia; SCF ubiquitin ligase; cancer vulnerability; replication stress; therapeutic target.

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