A new mode of DNA binding distinguishes Capicua from other HMG-box factors and explains its mutation patterns in cancer

• DOI: 10.1371/journal.pgen.1006622
• Publication Date: 2017-03-09T18:27:42Z
• Authors: Marta Forés; Lucía Simón-Carrasco; Leiore Ajuria; Núria Samper; Sergio González-C...; Matthias Drosten; Mariano Barbacid; Gerardo Jiménez
• Keywords: HMG-box; DNA binding site; High-mobility group

HMG-box proteins, including Sox/SRY (Sox) and TCF/LEF1 (TCF) family members, bind DNA via their HMG-box. This binding, however, is relatively weak both Sox TCF factors employ distinct mechanisms for enhancing affinity specificity DNA. Here we report that Capicua (CIC), an transcriptional repressor involved in Ras/MAPK signaling cancer progression, employs additional mode of binding enables selective recognition its targets. We find that, contrary to previous assumptions, the CIC does not alone but instead requires a distant motif (referred as C1) present at C-terminus all proteins. The C1 domains are necessary specific TGAATGAA-like sites, do function dimerization, active absence cofactors, suggesting they form bipartite structure sequence-specific demonstrate this mechanism operates throughout Drosophila development human cells, ensuring regulation multiple It thus appears proteins generally depend on auxiliary regulating appropriate genomic targets, each sub-family has evolved unique strategies purpose. Finally, key role also explains fact domain hotspot inactivating mutations oligodendroglioma other tumors, while being preserved oncogenic CIC-DUX4 fusion chimeras associated Ewing-like sarcomas.