A Dbf4p BRCT-like domain required for the response to replication fork arrest in budding yeast

Dbf4p is an essential regulatory subunit of the Cdc7p kinase required for the initiation of DNA replication. Cdc7p and Dbf4p orthologs have also been shown to function in the response to DNA damage. A previous Dbf4p multiple sequence alignment identified a conserved ~40 residue N-terminal region with similarity to the BRCT (BRCA1 C-terminal) motif called "motif N". BRCT motifs encode ~100 amino acid domains involved in the DNA damage response. We have identified an expanded and conserved ~100 residue N-terminal region of Dbf4p that includes motif N but is capable of encoding a single BRCT-like domain. Dbf4p orthologs diverge from the BRCT motif at the C-terminus but may encode a similar secondary structure in this region. We have therefore called this the BRDF motif (for BRCT and DBF4 similarity). The principal role of this Dbf4p motif was in the response to replication fork (RF) arrest, however, it was not required for cell cycle progression, activation of Cdc7p kinase activity, or interaction with the origin recognition complex (ORC) postulated to recruit Cdc7p-Dbf4p to origins. Rad53p likely directly phosphorylated Dbf4p in response to RF arrest and Dbf4p was required for Rad53p abundance. Rad53p and Dbf4p therefore cooperated to coordinate a robust cellular response to RF arrest.

Key Words: Cdc7 kinase, DNA damage, DNA replication, checkpoint

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