These proteins mediate significant antiviral activity23 as well as resistance to DNA damage in cancer cells.24,25 Our study of the U-STAT1-U-STAT2 dimer, including structural insights together with demonstration of biochemical and biological significance, provides a greatly expanded understanding of the detailed regulation of IFN-dependent signaling, especially seemingly paradoxical functions of the STAT1-STAT2 dimer as a positive or negative regulator of cytokine responses, depending on the conformation. Here, STAT2 is linked to cancer.