Depletion of the cell cycle/DNA damage checkpoint proteins CDC2 and CHEK1, like IFITM3, appeared to promote viral protein production and cytopathic response, while impairing assembly of infection-competent viral particles. A global comparison of the candidate modulators of H1N1 pathogenicity identified here with two whole-genome siRNA screens for modulators of cell cycle progression revealed a significant intersection ( Figure 3A ). However, CDC2 and CHEK1 depletion show quite distinct consequences on G1 versus G2 arrest suggesting their contribution to H1N1 infection may be independent of cell cycle control. CHEK1 has not been previously isolated in viral pathogenicity or viral replication screens, including those performed with the same siRNA library employed here ( Figure 3B , C, Tables 3 and 4 in Supporting Information S1). To investigate additional biological processes that may be associated with CHEK1 modulation of viral infection, we assembled a context-specific protein-protein interaction sub-network defined by the genomic Z-score distribution of the primary screen ( Figure S7 ). This subnetwork revealed the circadian gene Timeless, recently defined as a master regulator of the host defense response [20] , within the first-degree neighborhood of CHEK1 ( Figure 3D ). Given this association, we investigated the consequence of chemical inhibition of CHEK1 on H1N1 infection.