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). 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. Intriguingly, yeast Mec1 ATR- and Tel1 ATM-dependent phosphorylation promotes Rad51 protein stability during DDR, revealing how Mec1 ATR can alleviate proteotoxic stress. Defects in HR and DDR trigger genome instability and result in cancer predisposition, infertility, developmental defects, neurological diseases or premature aging. Unrepaired DSBs and ssDNA also activate Mec1 ATR and Tel1 ATM family kinases to initiate the DNA damage response (DDR) that safeguards genomic integrity. 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. 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.
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