ATM/ATR-like protein kinases play central roles in the maintenance of genome stability and phosphorylate numerous substrates in response to DNA damage, preferentially on SQ or TQ motifs. ATM/ATR substrates often contain several closely spaced SQ/TQ motifs in regions that have been termed SQ/TQ cluster domains (SCDs). SCDs are now considered a structural hallmark of DNA-damage-response proteins. Mutational analyses of a number of SCD-containing proteins indicate that multisite phosphorylation of SQ/TQ motifs is required for normal DNA-damage responses, most commonly by mediating protein-protein interactions in the formation of DNA-damage-induced complexes. SCD sequences are highly diverse and these domains may be largely unfolded in their native state rather than adopting a common three-dimensional fold. Structural disorder of SCDs could be advantageous for efficient phosphorylation by ATM/ATR kinases and also enable them to be molded into distinct conformations to facilitate flexible interactions with multiple binding partners.
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