MassIVE MSV000092004

Partial Public

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

Description

Oncogene-induced replication stress constitutes an early obstacle for pre-cancerous cells to overcome to progress towards malignancy. Fanconi anaemia signalling represents a major genomic maintenance pathway that is activated in response to replication stress, impinging on stalled replication fork stability and recovery. Here, we report that FBXL12 ubiquitinates the central Fanconi anaemia protein FANCD2 at stalled replication forks upon CHK1-mediated phosphorylation, resulting in FANCD2 degradation. This mechanism is required to promote efficient and faithful DNA replication under conditions of cyclin E- and drug-induced replication stress. In the absence of FBXL12, FANCD2 becomes trapped on chromatin leading to replication stress, excessive DNA damage, and cell death. In human cancers, FBXL12, cyclin E, and Fanconi anaemia signalling are positively correlated and upregulation or amplification of FBXL12 is linked to reduced survival in patients with high cyclin E expressing breast tumours. Finally, depletion of FBXL12 exacerbated oncogene-induced replication stress and sensitised breast cancer cells to drug-induced replication stress by WEE1 inhibition. Collectively, our results indicate that FBXL12 constitutes a vulnerability of cyclin E- overexpressing cancer cells and represents a novel target for cancer therapy. [doi:10.25345/C5BN9XC91] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: FBXL12, SCF, Fanconi anaemia, FANCD2, cyclin E, replication stress, AZD1775

Contact

Principal Investigators:
(in alphabetical order)
Andra Brunner, Karolinska Institutet, Sweden
Olle Sangfelt, Karolinska Institutet, Sweden
Submitting User: adarshmayank
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