<i>Tb</i>
            RAP1 has an unusual duplex DNA binding activity required for its telomere localization and VSG silencing

Afrin, Marjia; Gaurav, Amit Kumar; Yang, Xian Mei; Pan, Xiumei; Zhao, Yanxiang; Li, Bibo

doi:10.1126/sciadv.abc4065

Cited by 14 publications

(74 citation statements)

References 44 publications

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“…Rather, we recently identified both dsDNA and ssDNA binding activities in TbRAP1 (Afrin et al, 2020a). Both activities are electrostatic-based and require a positively charged 737 RKRRR 741 patch that overlaps with the nuclear localization signal (NLS) in the Myb-Like domain of TbRAP1 (Figure 3; Yang et al, 2009;Afrin et al, 2020a). Proteomic studies detected phosphorylated S742 and S744 residues in T. brucei cells (Nett et al, 2009;Urbaniak et al, 2013).…”

Section: Rap1 Homologs In Vertebrates Yeasts and T Bruceimentioning

confidence: 99%

“…Subtelomeric plasticity and relative frequent subtelomere recombination in these microbial pathogens is expected to help increase the diversity of their major surface antigen and enhance the effectiveness of evading host immune responses. As described above, in T. brucei, removal of telomere proteins (such as TbTRF, TbTIF2-a TbTRF-interacting factor and the human TIN2 homolog, and TbRAP1) leads to telomere instability and increased VSG switching rates (Jehi et al, 2014a,b;Nanavaty et al, 2017;Afrin et al, 2020a). Subtelomere instability has also been frequently observed in P. falciparum that causes malaria in humans.…”

Section: Scrap1mentioning

confidence: 99%

“…The T. brucei telomere complex is also essential for maintaining genome stability in this unicellular organism ( Li et al, 2005 ; Jehi et al, 2014a , b ; Nanavaty et al, 2017 ; Afrin et al, 2020a ), although the detailed underlying mechanisms are not exactly the same as that in mammalian and yeast cells (see below). Interestingly, T. brucei harbors important virulence genes encoding its major surface antigen at subtelomeres ( de Lange and Borst, 1982 ; Hertz-Fowler et al, 2008 ; Müller et al, 2018 ), and the telomere and subtelomere stability has been shown to influence the parasite’s pathogenesis mechanism ( Boothroyd et al, 2009 ; Hovel-Miner et al, 2012 ; Jehi et al, 2014a , b ; Nanavaty et al, 2017 ; Afrin et al, 2020a ). A better understanding of how these parasites maintain their genome stability and how they evade the host immune response will help their eventual elimination.…”

Section: Maintaining Telomere/subteloemere Stability and Antigenic Variation In Trypanosoma Bruceimentioning

confidence: 99%

“…Indeed, introducing a DSB at the active VSG vicinity can induce a 250-fold higher VSG switching rate ( Boothroyd et al, 2009 ; Glover et al, 2013 ). This is likely why the extremely short telomere downstream of the active VSG in telomerase negative cells ( Hovel-Miner et al, 2012 ) and depletion of several telomere proteins that diminish telomere integrity/stability lead to increased VSG switching frequencies ( Jehi et al, 2014a , b , 2016 ; Nanavaty et al, 2017 ; Afrin et al, 2020a ).…”

Section: Maintaining Telomere/subteloemere Stability and Antigenic Variation In Trypanosoma Bruceimentioning

confidence: 99%

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Keeping Balance Between Genetic Stability and Plasticity at the Telomere and Subtelomere of Trypanosoma brucei

2021

Front. Cell Dev. Biol.

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Telomeres, the nucleoprotein complexes at chromosome ends, are well-known for their essential roles in genome integrity and chromosome stability. Yet, telomeres and subtelomeres are frequently less stable than chromosome internal regions. Many subtelomeric genes are important for responding to environmental cues, and subtelomeric instability can facilitate organismal adaptation to extracellular changes, which is a common theme in a number of microbial pathogens. In this review, I will focus on the delicate and important balance between stability and plasticity at telomeres and subtelomeres of a kinetoplastid parasite, Trypanosoma brucei, which causes human African trypanosomiasis and undergoes antigenic variation to evade the host immune response. I will summarize the current understanding about T. brucei telomere protein complex, the telomeric transcript, and telomeric R-loops, focusing on their roles in maintaining telomere and subtelomere stability and integrity. The similarities and differences in functions and underlying mechanisms of T. brucei telomere factors will be compared with those in human and yeast cells.

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Section: Rap1 Homologs In Vertebrates Yeasts and T Bruceimentioning

confidence: 99%

Section: Scrap1mentioning

confidence: 99%

Section: Maintaining Telomere/subteloemere Stability and Antigenic Variation In Trypanosoma Bruceimentioning

confidence: 99%

Section: Maintaining Telomere/subteloemere Stability and Antigenic Variation In Trypanosoma Bruceimentioning

confidence: 99%

See 2 more Smart Citations

Keeping Balance Between Genetic Stability and Plasticity at the Telomere and Subtelomere of Trypanosoma brucei

2021

Front. Cell Dev. Biol.

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“…In addition, T. brucei telomere has a short 3' single-stranded G-rich overhang (10,11). The telomere structure and telomere proteins are not only essential for T. brucei genome stability and cell proliferation (36) but are also essential for monoallelic VSG expression (37)(38)(39)(40) and influence the VSG switching frequency (41)(42)(43)(44). However, detailed T. brucei telomere synthesis mechanisms are still not clear.…”

Section: Introductionmentioning

confidence: 99%

Trypanosoma bruceiPolIE suppresses telomere recombination

Tonini

Rabbani

Afrin

et al. 2021

Preprint

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Telomeres are essential for genome integrity and stability. In T. brucei that causes human African trypanosomiasis, the telomere structure and telomere proteins also influence the virulence of the parasite, as its major surface antigen involved in the host immune evasion is expressed exclusively from loci immediately upstream of the telomere repeats. However, telomere maintenance mechanisms are still unclear except that telomerase-mediated telomere synthesis is a major player. We now identify PolIE as an intrinsic telomere complex component. We find that depletion of PolIE leads to an increased amount of telomere/subtelomere DNA damage, an elevated rate of antigenic variation, and an increased amount of telomere T-circles and C-circles, indicating that PolIE suppresses telomere recombination and helps maintain telomere integrity. In addition, we observe much longer telomere G-rich 3 prime overhangs in PolIE-depleted cells, which is not dependent on telomerase. Furthermore, the level of telomere DNA synthesis is slightly increased in PolIE-depleted cells, which is dependent on telomerase. Therefore, we identify PolIE as a major player for telomere maintenance in T. brucei.

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The RRM-mediated RNA binding activity in T. brucei RAP1 is essential for VSG monoallelic expression

et al. 2023

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Trypanosoma brucei is a protozoan parasite that causes human African trypanosomiasis. Its major surface antigen VSG is expressed from subtelomeric loci in a strictly monoallelic manner. We previously showed that the telomere protein TbRAP1 binds dsDNA through its 737RKRRR741 patch to silence VSGs globally. How TbRAP1 permits expression of the single active VSG is unknown. Through NMR structural analysis, we unexpectedly identify an RNA Recognition Motif (RRM) in TbRAP1, which is unprecedented for RAP1 homologs. Assisted by the 737RKRRR741 patch, TbRAP1 RRM recognizes consensus sequences of VSG 3’UTRs in vitro and binds the active VSG RNA in vivo. Mutating conserved RRM residues abolishes the RNA binding activity, significantly decreases the active VSG RNA level, and derepresses silent VSGs. The competition between TbRAP1’s RNA and dsDNA binding activities suggests a VSG monoallelic expression mechanism in which the active VSG’s abundant RNA antagonizes TbRAP1’s silencing effect, thereby sustaining its full-level expression.

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Tb RAP1 has an unusual duplex DNA binding activity required for its telomere localization and VSG silencing

Cited by 14 publications

References 44 publications

Keeping Balance Between Genetic Stability and Plasticity at the Telomere and Subtelomere of Trypanosoma brucei

Keeping Balance Between Genetic Stability and Plasticity at the Telomere and Subtelomere of Trypanosoma brucei

Trypanosoma bruceiPolIE suppresses telomere recombination

The RRM-mediated RNA binding activity in T. brucei RAP1 is essential for VSG monoallelic expression

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