RAD51-mediated R-loop formation acts to repair transcription-associated DNA breaks driving antigenic variation in Trypanosoma brucei .

Autor:	Girasol MJ; College of Medical, Veterinary and Life Sciences, School of Infection and Immunity, Wellcome Centre for Integrative Parasitology, University of Glasgow, Glasgow G12 8TA, United Kingdom.; Faculty of the MD-PhD in Molecular Medicine Program, College of Medicine, University of the Philippines Manila, Manila 1000, Philippines., Krasilnikova M; College of Medical, Veterinary and Life Sciences, School of Infection and Immunity, Wellcome Centre for Integrative Parasitology, University of Glasgow, Glasgow G12 8TA, United Kingdom., Marques CA; College of Medical, Veterinary and Life Sciences, School of Infection and Immunity, Wellcome Centre for Integrative Parasitology, University of Glasgow, Glasgow G12 8TA, United Kingdom., Damasceno JD; College of Medical, Veterinary and Life Sciences, School of Infection and Immunity, Wellcome Centre for Integrative Parasitology, University of Glasgow, Glasgow G12 8TA, United Kingdom., Lapsley C; College of Medical, Veterinary and Life Sciences, School of Infection and Immunity, Wellcome Centre for Integrative Parasitology, University of Glasgow, Glasgow G12 8TA, United Kingdom., Lemgruber L; College of Medical, Veterinary and Life Sciences, School of Infection and Immunity, Wellcome Centre for Integrative Parasitology, University of Glasgow, Glasgow G12 8TA, United Kingdom., Burchmore R; College of Medical, Veterinary and Life Sciences, School of Infection and Immunity, Wellcome Centre for Integrative Parasitology, University of Glasgow, Glasgow G12 8TA, United Kingdom., Beraldi D; College of Medical, Veterinary and Life Sciences, School of Infection and Immunity, Wellcome Centre for Integrative Parasitology, University of Glasgow, Glasgow G12 8TA, United Kingdom., Carruthers R; College of Medical, Veterinary and Life Sciences, School of Cancer Sciences, University of Glasgow, Glasgow G12 0YN, United Kingdom., Briggs EM; College of Medical, Veterinary and Life Sciences, School of Infection and Immunity, Wellcome Centre for Integrative Parasitology, University of Glasgow, Glasgow G12 8TA, United Kingdom.; Institute for Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3FL, United Kingdom., McCulloch R; College of Medical, Veterinary and Life Sciences, School of Infection and Immunity, Wellcome Centre for Integrative Parasitology, University of Glasgow, Glasgow G12 8TA, United Kingdom.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2023 Nov 28; Vol. 120 (48), pp. e2309306120. Date of Electronic Publication: 2023 Nov 21.
DOI:	10.1073/pnas.2309306120
Abstrakt:	RNA-DNA hybrids are epigenetic features of all genomes that intersect with many processes, including transcription, telomere homeostasis, and centromere function. Increasing evidence suggests that RNA-DNA hybrids can provide two conflicting roles in the maintenance and transmission of genomes: They can be the triggers of DNA damage, leading to genome change, or can aid the DNA repair processes needed to respond to DNA lesions. Evasion of host immunity by African trypanosomes, such as Trypanosoma brucei , relies on targeted recombination of silent Variant Surface Glycoprotein ( VSG ) genes into a specialized telomeric locus that directs transcription of just one VSG from thousands. How such VSG recombination is targeted and initiated is unclear. Here, we show that a key enzyme of T. brucei homologous recombination, RAD51, interacts with RNA-DNA hybrids. In addition, we show that RNA-DNA hybrids display a genome-wide colocalization with DNA breaks and that this relationship is impaired by mutation of RAD51. Finally, we show that RAD51 acts to repair highly abundant, localised DNA breaks at the single transcribed VSG and that mutation of RAD51 alters RNA-DNA hybrid abundance at 70 bp repeats both around the transcribed VSG and across the silent VSG archive. This work reveals a widespread, generalised role for RNA-DNA hybrids in directing RAD51 activity during recombination and uncovers a specialised application of this interplay during targeted DNA break repair needed for the critical T. brucei immune evasion reaction of antigenic variation. Competing Interests: Competing interests statement:The authors declare no competing interest.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu