Using the nematode worm as a model system, we have identified the circadian protein CLK-2 and ATL-1 (C. elegans ATR) as factors that coimmunoprecipitate with C. elegans FANCD2 (FCD-2) following ICL damage. C. elegans atl-1 and clk-2 mutants and siRNA depletion of human hCLK2 (KIAA00693) compromises FCD-2/FANCD2 recruitment to blocked replication forks and confers ICL sensitivity, a hallmark of FA. Cells deficient for hCLK2 are also defective for damage-induced mono-ubiquitylation of FANCD2 and exhibit radio-resistant DNA synthesis indicative of an S-phase checkpoint defect. ATR activation leading to BRCA1-mediated ubiquitylation remains intact in hCLK2 depleted cells, yet ATR-dependent phosphorylation of Chk1 and Claspin is severely attenuated following S-phase insults. Finally, recruitment of the homologous recombination factor RAD51 is also impaired in cells depleted of hCLK2, which leads to a reduced homologous recombination frequency at sites of DNA damage.