1. A kinetochore-based ATM/ATR-independent DNA damage checkpoint maintains genomic integrity in trypanosomes
- Author
-
Ziyin Li, Yasuhiro Kurasawa, Huiqing Hu, Qing Zhou, and Kieu T. M. Pham
- Subjects
Trypanosoma ,Cell cycle checkpoint ,Chromosomal Proteins, Non-Histone ,Trypanosoma brucei brucei ,Aurora B kinase ,Protozoan Proteins ,Cell Cycle Proteins ,Ataxia Telangiectasia Mutated Proteins ,Biology ,Genome Integrity, Repair and Replication ,Genomic Instability ,03 medical and health sciences ,0302 clinical medicine ,Cyclins ,Genetics ,Humans ,Kinetochores ,Metaphase ,030304 developmental biology ,0303 health sciences ,Cohesin ,Kinetochore ,Cell Cycle Checkpoints ,Cell cycle ,G2-M DNA damage checkpoint ,Cell biology ,Spindle checkpoint ,biological phenomena, cell phenomena, and immunity ,Genome, Protozoan ,030217 neurology & neurosurgery ,DNA Damage - Abstract
DNA damage-induced cell cycle checkpoints serve as surveillance mechanisms to maintain genomic stability, and are regulated by ATM/ATR-mediated signaling pathways that are conserved from yeast to humans. Trypanosoma brucei, an early divergent microbial eukaryote, lacks key components of the conventional DNA damage-induced G2/M cell cycle checkpoint and the spindle assembly checkpoint, and nothing is known about how T. brucei controls its cell cycle checkpoints. Here we discover a kinetochore-based, DNA damage-induced metaphase checkpoint in T. brucei. MMS-induced DNA damage triggers a metaphase arrest by modulating the abundance of the outer kinetochore protein KKIP5 in an Aurora B kinase- and kinetochore-dependent, but ATM/ATR-independent manner. Overexpression of KKIP5 arrests cells at metaphase through stabilizing the mitotic cyclin CYC6 and the cohesin subunit SCC1, mimicking DNA damage-induced metaphase arrest, whereas depletion of KKIP5 alleviates the DNA damage-induced metaphase arrest and causes chromosome mis-segregation and aneuploidy. These findings suggest that trypanosomes employ a novel DNA damage-induced metaphase checkpoint to maintain genomic integrity.
- Published
- 2019