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