DNA Repair Mechanisms in Trypanosomatid Parasites

Trypanosomatid parasites employ a sophisticated array of DNA repair pathways to preserve genome integrity while navigating the stresses of host immunity and rapid antigenic variation. The predominant mechanism is homologous recombination, driven by the RAD51 recombinase and assisted by parasite-specific expansions of BRCA2 BRC repeats, which accurately repair double-strand breaks using homologous templates. Histone H2A phosphorylation marks sites of damage and orchestrates cell cycle checkpoints, ensuring lesions are addressed before mitosis. Transcription–replication conflicts generate RNA–DNA hybrid structures (R-loops) that both provoke and direct repair activities, particularly at subtelomeric variant surface glycoprotein (VSG) expression sites. Origin of replication usage varies among species, with Orc1/Cdc6-dependent initiation linked to antigenic gene clusters and epigenetic landscape. Collectively, these repair strategies underpin antigenic switching, genome plasticity and parasite survival, offering potential targets for chemotherapeutic intervention against Chagas disease, African trypanosomiasis and leishmaniasis.

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DNA Repair Mechanisms in Trypanosomatid Parasites publication trend

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Technical terms

Homologous recombination: Repair mechanism that uses a homologous DNA sequence as a template to accurately restore double-strand breaks.

R-loop: A three-strand nucleic acid structure in which an RNA transcript hybridises with its complementary DNA, displacing the non-template strand.

Double-strand break: A form of DNA damage involving simultaneous discontinuities in both strands of the helix.

Replication origin: A genomic site where DNA replication is initiated by the assembly of key replication proteins.

Phosphoproteomics: Large-scale study of protein phosphorylation states to elucidate signalling networks in response to cellular events.

References

1. RAD51-mediated R-loop formation acts to repair transcription-associated DNA breaks driving antigenic variation in Trypanosoma brucei. Proceedings of the National Academy of Sciences of the United States of America (2023).
2. Integrating high-throughput analysis to create an atlas of replication origins in Trypanosoma cruzi in the context of genome structure and variability. mBio (2024).
3. Phosphoproteomic analysis of the response to DNA damage in Trypanosoma brucei. Journal of Biological Chemistry (2024).
4. Trypanosomal histone γH2A and the DNA damage response. Molecular and Biochemical Parasitology (2012).
5. Trypanosoma brucei BRCA2 acts in antigenic variation and has undergone a recent expansion in BRC repeat number that is important during homologous recombination. Molecular Microbiology (2008).