YAP engages RIF1 to dampen replication stress in squamous cell carcinoma.

Squamous cancers are the most frequently diagnosed solid tumours world-wide. The closely related transcriptional co-regulators YAP and TAZ (WWTR1) have emerged as important drivers of tumour initiation and progression in various types of squamous cell carcinoma. How YAP and TAZ execute their oncogenic functions in squamous cancers is still not fully understood. Here, we report that in addition to controlling transcriptional programmes that determine the balance between proliferation and terminal differentiation, YAP also engages with RIF1, a key regulator of DNA replication timing and protector of stalled replication forks under replication stress. YAP modulates gene expression of RIF1 via TEAD transcription factors, and also stabilizes RIF1 protein on the chromatin. YAP-RIF1 complex formation increases in response to exogenous replication stress, and treatment with hydroxyurea to induce replication fork stalling acts synergistically with YAP depletion to impair cell proliferation. Our results thus demonstrate that YAP's oncogenic functions in squamous cell carcinoma involve both transcriptional and non-transcriptional mechanisms, and that RIF1 is key for squamous cell carcinoma cells to survive with their high levels of endogenous replication stress.