期刊
NUCLEIC ACIDS RESEARCH
卷 49, 期 10, 页码 5637-5653出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkab401
关键词
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资金
- NIH [R01 grant] [AI066095]
- NIH [S10 grant] [S10OD025252]
- GRHD at CSU
- NIH
- GRHD center at CSU
In this study, several unique features of TERRA and telomere biology in Trypanosoma brucei were identified. It was found that TERRA foci number is cell cycle-regulated and influenced by TbTRF. TbTRF binds TERRA through its C-terminal Myb domain in a sequence-specific manner, suppressing TERRA levels without affecting its half-life, and depletion of TbTRF leads to increased telomeric R-loop and telomere DNA damage.
Telomere repeat-containing RNA (TERRA) has been identified in multiple organisms including Trypanosoma brucei, a protozoan parasite that causes human African trypanosomiasis. T. brucei regularly switches its major surface antigen, VSG, to evade the host immune response. VSG is expressed exclusively from subtelomeric expression sites, and we have shown that telomere proteins play important roles in the regulation of VSG silencing and switching. In this study, we identify several unique features of TERRA and telomere biology in T. brucei. First, the number of TERRA foci is cell cycle-regulated and influenced by TbTRF, the duplex telomere DNA binding factor in T. brucei. Second, TERRA is transcribed by RNA polymerase I mainly from a single telomere downstream of the active VSG. Third, TbTRF binds TERRA through its C-terminal Myb domain, which also has the duplex DNA binding activity, in a sequence-specific manner and suppresses the TERRA level without affecting its half-life. Finally, levels of the telomeric R-loop and telomere DNA damage were increased upon TbTRF depletion. Overexpression of an ectopic allele of RNase H1 that resolves the R-loop structure in TbTRF RNAi cells can partially suppress these phenotypes, revealing an underlying mechanism of how TbTRF helps maintain telomere integrity.
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