Hippo pathway in the maintenance of genome integrity

Abstract

Genome instability resulting from accumulation of DNA lesions is not only a hallmark of cancer but also a driving force. Recently, pathways that are known to regulate cell growth or development have been shown to interplay with the canonical DNA damage response to promote repair efficacy and cancer free survival.

The Hippo pathway was originally studied for regulation of organ growth, however deregulation of the cascade can induce tumors in model organisms and occurs in a broad range of human carcinomas. Mostly studied for regulation of cell proliferation via inhibition of oncogenic transcriptional programs induced by the YAP/TAZ transcription co-factors, loss of Hippo function has been linked with tumor growth, perturbed cell polarity and metastasis.

We recently uncovered crosstalk between the Hippo pathway and the canonical DNA damage response. The pathway is a target of the ATM/ATR kinases and sensors of DNA lesions. We identify components of the cascade acting at the sites of DNA damage to promote genomic integrity. We detect Hippo kinase localized pools at nucleolar chromatin in the presence of rDNA breaks and stalled replication forks within heterochomatin. Overall our findings highlight a role for the Hippo pathway in chromatin areas prone to genomic instability.