Rad17 is an essential component of cell cycle checkpoints activated by DNA damage and disruption of DNA replication. DNA lesions such as single- and double-strand breaks, inter- and intra-strand cross-links, and base modifications hamper transcription and replication, resulting in cell cycle arrest, apoptosis, and mutagenesis. Phosphorylation of Rad17 at Ser635 and Ser645 is a critical early event during checkpoint signaling in DNA damaged cells.