casein-kinase-ii and Fanconi-Anemia

Interstrand crosslinks (ICLs) of the DNA helix are a deleterious form of DNA damage. ICLs can be repaired by the Fanconi anemia pathway. At the center of the pathway is the FANCD2/FANCI complex, recruitment of which to DNA is a critical step for repair. After recruitment, monoubiquitination of both FANCD2 and FANCI leads to their retention on chromatin, ensuring subsequent repair. However, regulation of recruitment is poorly understood. Here, we report a cluster of phosphosites on FANCD2 whose phosphorylation by CK2 inhibits both FANCD2 recruitment to ICLs and its monoubiquitination in vitro and in vivo. We have found that phosphorylated FANCD2 possesses reduced DNA binding activity, explaining the previous observations. Thus, we describe a regulatory mechanism operating as a molecular switch, where in the absence of DNA damage, the FANCD2/FANCI complex is prevented from loading onto DNA, effectively suppressing the FA pathway.

Topics: Amino Acid Sequence; Animals; Casein Kinase II; CRISPR-Cas Systems; DNA; DNA Damage; DNA Repair; Fanconi Anemia; Fanconi Anemia Complementation Group D2 Protein; Fanconi Anemia Complementation Group Proteins; HeLa Cells; Humans; Phosphorylation; Protein Binding; Protein Structure, Quaternary; RNA, Guide, Kinetoplastida; Sequence Alignment; Ubiquitination

Topics: Alternative Splicing; Amino Acid Sequence; Animals; Base Sequence; Casein Kinase II; Cattle; Cell Cycle Proteins; Cell Line; Cloning, Molecular; Conserved Sequence; DNA-Binding Proteins; DNA, Complementary; Exons; Fanconi Anemia; Fanconi Anemia Complementation Group C Protein; Fanconi Anemia Complementation Group Proteins; Female; Humans; Mice; Molecular Sequence Data; Nuclear Proteins; Open Reading Frames; Phosphorylation; Protein Kinase C; Protein Serine-Threonine Kinases; Proteins; Rats; Sequence Homology, Amino Acid