DDX21 is an RNA helicase protein with a diverse set of biological functions. Abnormal levels of DDX21 protein has been observed in colorectal and breast cancers as well as in schizophrenic patients, making it a potential therapeutic target. DDX21 can bind and unwind guanine-rich four-stranded structures of RNA referred to as guanine-quadruplexes (rG4s) and affect the translation of a reporter construct with an rG4 in its 5’ UTR. However, no biological rG4 targets of DDX1 are currently known. In our current study, we use shotgun proteomics to compare global protein expression of cells with wild type DDX21 and mutant DDX21 with impaired rG4s binding capability to identify potential binding targets of DDX21.