Researchers in Poland identified that the human protein TTC33 directly binds with WDR61 and PHF5A to form a core complex that helps preserve genomic integrity, according to a peer-reviewed study published in Nature Communications on August 21, 2026. TTC33 is an evolutionarily conserved tetratricopeptide repeat protein expressed across human tissues, though its molecular function was previously uncharacterized.
Using comparative label-free mass spectrometry, biochemical assays, structural modeling, and molecular dynamics, the scientists mapped what they named the TTC33-associated network. The network includes WDR61, CCDC97, UNG1/2, PP2A-B55α, PHF5A, and components of the SF3B U2 spliceosomal complex.
The TTC33 protein directly recruits WDR61 and PHF5A to assemble into a trimeric core complex designated as TANC. Once assembled, TANC forms distinct interactions with either UNG1/2 or the SF3B–CCDC97 complex. The experiments also established that WDR61 stabilizes TTC33 by shielding it against proteolytic degradation.
Somatic mutations in TTC33 at key interface residues reduce the stability of the TANC complex and weaken its interaction network. Cellular loss of these network components triggers genomic instability and activates DNA damage markers, including p53 phosphorylation and γH2AX.
Rafał Tomecki and Małgorzata Drabko contributed equally as lead authors on the study, collaborating with teams from the Institute of Biochemistry and Biophysics at the Polish Academy of Sciences and the University of Warsaw. The National Science Centre of Poland funded the investigation through OPUS grant 2022/45/B/NZ1/02654 and SONATA BIS grant 2017/26/E/NZ1/00724.
