The Eyes Absent family: At the intersection of DNA repair, mitosis, and replication.

The Eyes Absent family (EYA1–4) are a group of dual function proteins that act as both tyrosine phosphatases and transcriptional co-activators. EYA proteins play a vital role in development, but are also aberrantly overexpressed in cancers, where they often confer an oncogenic effect. Precisely how the EYAs impact cell biology is of growing interest, fuelled by the therapeutic potential of an expanding repertoire of EYA inhibitors. Recent functional studies suggest that the EYAs are important players in the regulation of genome maintenance pathways including DNA repair, mitosis, and DNA replication. While the characterized molecular mechanisms have predominantly been ascribed to EYA phosphatase activities, EYA co-transcriptional activity has also been found to impact the expression of genes that support these pathways. This indicates functional convergence of EYA phosphatase and co-transcriptional activities, highlighting the emerging importance of the EYA protein family at the intersection of genome maintenance mechanisms. In this review, we discuss recent progress in defining EYA protein substrates and transcriptional effects, specifically in the context of genome maintenance. We then outline future directions relevant to the field and discuss the clinical utility of EYA inhibitors. • EYA1–4 are dual function proteins with converging roles in genome maintenance. • The EYAs act as tyrosine phosphatases and can dephosphorylate H2AX, RAD51 and PLK1. • The EYAs also function as co-transcriptional activators of genes involved in genome maintenance. • EYA phosphatase and co-transcriptional inhibitors have emerging potential as cancer therapeutics. [ABSTRACT FROM AUTHOR]