Budding yeast Rad51: a paradigm for how phosphorylation and intrinsic structural disorder regulate homologous recombination and protein homeostasis

The RecA-family recombinase Rad51 is the central player in homologous recombination (HR), the faithful pathway for repairing DNA double-strand breaks (DSBs) during both mitosis and meiosis. The behavior of Rad51 protein in vivo is fine-tuned via posttranslational modifications conducted by multiple protein kinases in response to cell cycle cues and DNA lesions. Unrepaired DSBs and ssDNA also activate Mec1(ATR) and Tel1(ATM) family kinases to initiate the DNA damage response (DDR) that safeguards genomic integrity. Defects in HR and DDR trigger genome instability and result in cancer predisposition, infertility, developmental defects, neurological diseases or premature aging. Intriguingly, yeast Mec1(ATR)- and Tel1(ATM)-dependent phosphorylation promotes Rad51 protein stability during DDR, revealing how Mec1(ATR) can alleviate proteotoxic stress. Moreover, Mec1(ATR)- and Tel1(ATM)-dependent phosphorylation also occurs on DDR-unrelated proteins, suggesting that Mec1(ATR) and Tel1(ATM) have a DDR-independent function in protein homeostasis. In this minireview, we first describe how human and budding yeast Rad51 are phosphorylated by multiple protein kinases at different positions to promote homology-directed DNA repair and recombination (HDRR). Then, we discuss recent findings showing that intrinsic structural disorder and Mec1(ATR)/Tel1(ATM)-dependent phosphorylation are coordinated in yeast Rad51 to regulate both HR and protein homeostasis.