Extended Data Fig. 10: Recurrent mutations in domains of protein–DNA interaction.
From: Identification of cancer driver genes based on nucleotide context
Significance values in this figure legend were computed using MutPanning and adjusted for multiple testing (false discovery rate, FDR). Recurrent SOX17 mutations in endometrial cancer (n = 327 samples, FDR = 8.77 × 10−3) are located in the high-mobility-group box domain at the SOX17–DNA interface (PDB: 4A3N superposed with 3F27). POLR2A harbors recurrent mutations in lung adenocarcinoma (n = 446, FDR = 9.28 × 10−6) at the end of an alpha helical segment that is directly pointed at the major groove of the double stranded DNA (PDB: 5IYB). The open complex of a cryo-EM multicomponent structure where the melted single-stranded template DNA is inserted into the active site and RNA polymerase II locates the transcription start site is visualized. CEBPA harbors recurrent mutations in hematological malignancies (n = 1,018, FDR = 1.16 × 10−7) at the cross-over interface of the two CEBPA homodimers (PDB: 1NWQ). GATA3 (PDB: 4HCA) harbors recurrent mutations in breast cancer (n = 1,443, FDR < 10−20) at Asn334, which is located in the GATA-type 2 zinc finger (res317–res341), as well as the residue Met294, which is located peripheral to the GATA-type 1 zinc finger domain (res263–res287). RUNX1 harbors recurrent mutations in breast cancer (n = 1,443, FDR = 2.22 × 10−4) and hematological malignancies (n = 1018, FDR = 1.94 × 10−5). Arg174 plays an important role for DNA recognition and facilitates the formation of hydrogen bond interactions to a guanosine base from the consensus DNA binding sequence of RUNX1 (PDB: 1H9D).
