To maintain the integrity of the genome, cells have evolved a complex signalling system, termed the DNA damage response (DDR), which detects DNA damage and promotes DNA repair. To date, over 600 proteins have been identified that play an integral role in the DDR. RAD9, encoding a DDR mediator protein, was the prototypical DNA damage checkpoint gene, establishing the genetic regulation of transient cell-cycle delays upon DNA damage. Rad9, identified 38 years ago in the budding yeast Saccharomyces cerevisiae as a damage-dependent cell-cycle regulator, is now known to regulate additional responses to DNA damage including both cell-cycle recovery and repair. The Rad9 protein is extensively phosphorylated both during a normal cell cycle and following DNA damage and several of these modifications have been linked to specific Rad9 roles within the DDR. Proteins structurally and functionally related to Rad9 exist in mammalian cells (e.g., 53BP1, BRCA1, MDC1) and insights into their regulation and mechanism of action have been informed by studies in yeast. This review will discuss the cellular mechanisms governing the DDR with an emphasis on the multifaceted role of Rad9 in sensing and responding to DNA damage, and how phosphorylation events regulate its function within the DDR. As the cellular events governing the DDR are well conserved, discoveries in yeast can be extrapolated to humans and may lead to the identification of additional novel protein targets, with several DDR inhibitors currently in clinical use or showing promise in clinical trials.
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