Novel clades of the HU/IHF superfamily point to unexpected roles in the eukaryotic centrosome, chromosome partitioning, and biologic conflicts.

The HU superfamily of proteins, with a unique DNA-binding mode, has been extensively studied as the primary chromosome-packaging protein of the bacterial superkingdom. Representatives also play a role in DNA-structuring during recombination events and in eukaryotic organellar genome maintenance. However, beyond these well-studied roles, little is understood of the functional diversification of this large superfamily. Using sensitive sequence and structure analysis methods we identify multiple novel clades of the HU superfamily. We present evidence that a novel eukaryotic clade prototyped by the human CCDC81 protein acquired roles beyond DNA-binding, likely in protein-protein interaction in centrosome organization and as a potential cargo-binding protein in conjunction with Dynein-VII. We also show that these eukaryotic versions were acquired via an early lateral transfer from bacteroidetes, where we predict a role in chromosome partition. This likely happened before the last eukaryotic common ancestor, pointing to potential endosymbiont contributions beyond that of the mitochondrial progenitor. Further, we show that the dramatic lineage-specific expansion of this domain in the bacteroidetes lineage primarily is linked to a functional shift related to potential recognition and preemption of genome invasive entities such as mobile elements. Remarkably, the CCDC81 clade has undergone a similar massive lineage-specific expansion within the archosaurian lineage in birds, suggesting a possible use of the HU superfamily in a similar capacity in recognition of non-self molecules even in this case.