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

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 and both sox and tcf factors employ distinct mechanisms for enhancing their affinity and specificity for dna. here we report that capicua (cic),an hmg-box transcriptional repressor involved in ras/mapk signaling and cancer progression,employs an additional distinct mode of dna binding that enables selective recognition of its targets. we find that,contrary to previous assumptions,the hmg-box of cic does not bind dna alone but instead requires a distant motif (referred to as c1) present at the c-terminus of all cic proteins. the hmg-box and c1 domains are both necessary for binding specific tgaatgaa-like sites,do not function via dimerization,and are active in the absence of cofactors,suggesting that they form a bipartite structure for sequence-specific binding to dna. we demonstrate that this binding mechanism operates throughout drosophila development and in human cells,ensuring specific regulation of multiple cic targets. it thus appears that hmg-box proteins generally depend on auxiliary dna binding mechanisms for regulating their appropriate genomic targets,but that each sub-family has evolved unique strategies for this purpose. finally,the key role of c1 in dna binding also explains the fact that this domain is a hotspot for inactivating mutations in oligodendroglioma and other tumors,while being preserved in oncogenic cic-dux4 fusion chimeras associated to ewing-like sarcomas. © 2017 forés et al.