Cdc2-related kinases and cyclin partners as regulators of the Trypanosoma brucei cell cycle: Current evidence and unresolved questions.

Trypanosoma brucei, the protozoan parasite responsible for African trypanosomiasis, undergoes a divergent cell cycle characterized by closed mitosis, inheritance of single-copy organelles such as the kinetoplast, basal body, and flagellum, and anterior-to-posterior longitudinal cytokinesis. Cdc2-related kinases (CRKs) and cyclin-like proteins have emerged as key regulators of these processes; however, most CRK- cyclin modules remain incompletely defined in terms of their in vivo composition, substrate specificity, and physiological function. In this review, we summarize current evidence for the roles of T. brucei CRKs in parasite cell-cycle control, focusing on CRK1-associated PHO80-like cyclins in G1/S progression, the CRK2-CYC13 complex in S-phase DNA replication, CRK3-associated complexes in mitosis, and additional modules including CRK9-CYC12 in spliced-leader trans-splicing and CRK12-CYC9 with endocytic and cytokinesis-related phenotypes. By comparing evidence across these modules, we highlight the gap between phenotypic assignment and mechanistic validation, and emphasize the need to define functional CRK-cyclin-substrate axes in vivo. Resolving these gaps will provide important insights into parasite-specific cell-cycle control and support the evaluation of CRKs as parasite-selective therapeutic targets.