Pof8 is a La-related protein and a constitutive component of telomerase in fission yeast

Páez-Moscoso, Diego J.; Pan, Lili; Sigauke, Rutendo F; Schroeder, Morgan R.; Tang, Wen; Baumann, Peter

doi:10.1038/s41467-017-02284-8

Cited by 30 publications

(65 citation statements)

References 48 publications

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“…Members of the LARP7 family are the closest relatives to genuine La and like La, contain an N-terminal La module and C-terminal atypical RRM (xRRM), but unlike genuine La, they bind a single cognate RNA. In ciliates Tetrahymena thermophila and Euplotes aediculatus and fission yeast, the LARP7 family proteins p65, p43, and Pof8, respectively, bind telomerase RNA (TER) and promote hierarchal assembly of the telomerase ribonucleoprotein (RNP) particle (11)(12)(13)(14)(15). In metazoa, the LARP7 family protein Larp7 binds the 7SK long noncoding RNA (lncRNA) and is required to protect 7SK from degradation and for hierarchal assembly of the 7SK RNP (16,17).…”

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confidence: 99%

Structural basis for recognition of human 7SK long noncoding RNA by the La-related protein Larp7

Eichhorn

Yang

Repeta

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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The La and the La-related protein (LARP) superfamily is a diverse class of RNA binding proteins involved in RNA processing, folding, and function. Larp7 binds to the abundant long noncoding 7SK RNA and is required for 7SK ribonucleoprotein (RNP) assembly and function. The 7SK RNP sequesters a pool of the positive transcription elongation factor b (P-TEFb) in an inactive state; on release, P-TEFb phosphorylates RNA Polymerase II to stimulate transcription elongation. Despite its essential role in transcription, limited structural information is available for the 7SK RNP, particularly for protein-RNA interactions. Larp7 contains an N-terminal La module that binds UUU-3'OH and a C-terminal atypical RNA recognition motif (xRRM) required for specific binding to 7SK and P-TEFb assembly. Deletion of the xRRM is linked to gastric cancer in humans. We report the 2.2-Å X-ray crystal structure of the human La-related protein group 7 (hLarp7) xRRM bound to the 7SK stem-loop 4, revealing a unique binding interface. Contributions of observed interactions to binding affinity were investigated by mutagenesis and isothermal titration calorimetry. NMR C spin relaxation data and comparison of free xRRM, RNA, and xRRM-RNA structures show that the xRRM is preordered to bind a flexible loop 4. Combining structures of the hLarp7 La module and the xRRM-7SK complex presented here, we propose a structural model for Larp7 binding to the 7SK 3' end and mechanism for 7SK RNP assembly. This work provides insight into how this domain contributes to 7SK recognition and assembly of the core 7SK RNP.

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confidence: 99%

Structural basis for recognition of human 7SK long noncoding RNA by the La-related protein Larp7

Eichhorn

Yang

Repeta

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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“…Recently, a LARP7-like protein (Pof8) was described in Schizosaccharomyces pombe and in a few Taphrinomycotina sister species [10][11][12]. Primary sequence homology of Pof8 to other eukaryotic LARP7s is limited to the RRM2 region and consequently, Pof8 LaM was only inferred from secondary structure predictions.…”

Section: Discussionmentioning

confidence: 99%

“…LARP7s are present in all animals and in Amoebozoa (HaLARP7, DdLARP7), Alveolates (EaLARP7, SleLARP7, ThLARP7) and Stramenopiles (PsLARP7, TcLARP7) ( Figure 5), but not all LARP7s belonging to these three later lineages host a conserved RRM2 region. Recently, several reports described the presence of a LARP7 (named Pof8) in fission yeast [10][11][12]. The only significant primary sequence conservation between Pof8 and other eukaryote LARP7s resides in the short RRM2 region, and the presence of a LaM (La motif/ RRM1) can only be inferred from secondary sequence predictions.…”

Section: Larp7mentioning

confidence: 99%

“…Genuine La proteins have been shown to protect the 3ʹ-end of nascent RNA polymerase III transcripts and, in many occasions, to act as an RNA chaperone to prevent RNA misfolding [4,5]. La-Related Protein (LARP) 7 targets specialized non-coding RNAs (Vertebrates 7SK [6,7] or Ciliates [8,9] and Fungi [10][11][12] telomerase RNA) to promote their assembly into a functional ribonucleoprotein complex. Other LARPs (1, 4 and 6), as well as the cytoplasmic isoform of the genuine La, target mRNAs and regulate their cellular localization, stability and translation potential [13][14][15][16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

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Distribution, organization an evolutionary history of La and LARPs in eukaryotes

Deragon

2020

RNA Biology

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The fate of any cellular RNA is largely influenced by the nature and diversity of its interactions with various RNA-binding proteins (RBPs) leading to the formation of a biologically significant ribonucleoprotein (RNP) complex. La motif-containing proteins (composed of genuine La and La-related proteins (LARPs)) represent an evolutionary conserved family of RBPs that encompass a large range of crucial functions, involving coding and non-coding RNAs. In this work, we provide data that extend our previous knowledge on the distribution, organization and evolutionary history of this important protein family. Using a repertoire of 345 La motifcontaining proteins from 135 species representing all major eukaryotic lineages, we were able to pinpoint many lineage-specific variations in the structural organization of La and LARPs and propose new evolutive scenarios to explain their modern genomic distribution.

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“…Telomere extension has been shown to occur preferentially at short telomeres (TEIXEIRA et al 2004), likely due to increased telomerase recruitment (BIANCHI AND SHORE 2007;CHANG et al 2007;SABOURIN et al 2007;CHANG et al 2013). The fission yeast telomerase is comprised of the conserved catalytic subunit Trt1 (NAKAMURA et al 1997), the RNA component TER1 that encodes the template for addition of the degenerate telomeric repeat to support telomere elongation (LEONARDI et al 2008;WEBB AND ZAKIAN 2008), the conserved subunit Est1 (BEERNINK et al 2003), and accessory factors such as the Lsm proteins (NAKAMURA et al 1997;BEERNINK et al 2003;LEONARDI et al 2008;WEBB AND ZAKIAN 2008;TANG et al 2012) and the La-like protein LARP7/Pof8 MENNIE et al 2018;PAEZ-MOSCOSO et al 2018). In fission yeast, the factor Ccq1 links telomerase recruitment to the 3' telomeric overhang through Tpz1 and Pot1 to support telomere maintenance (MIYOSHI et al 2008;TOMITA AND COOPER 2008).…”

Section: Introductionmentioning

confidence: 99%

RNA-DNA hybrids support recombination-based telomere maintenance in fission yeast

Bennett

Liu

et al. 2018

Preprint

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Running Title: Telomere maintenance by recombination Keywords: telomere / recombination / RNA-DNA hybrid / TERRA / shelterin / ALT pathway 2 ABSTRACT A subset of cancers rely on telomerase-independent mechanisms to maintain their chromosome ends. The predominant "alternative lengthening of telomeres" pathway appears dependent on homology-directed repair (HDR) to maintain telomeric DNA. However, the molecular changes needed for cells to productively engage in telomeric HDR are poorly understood. To gain new insights into this transition, we monitored the state of telomeres during serial culture of fission yeast (Schizosaccharomyces pombe) lacking the telomerase recruitment factor Ccq1. Rad52 is loaded onto critically short telomeres shortly after germination despite continued telomere erosion, suggesting that recruitment of recombination factors is not sufficient to maintain telomeres in the absence of telomerase function. Instead, survivor formation coincides with the derepression of telomeric repeat-containing RNA (TERRA). In this context, degradation of TERRA associated with the telomere in the form of R-loops drives a severe growth crisis, ultimately leading to a novel type of survivor with linear chromosomes and altered cytological telomere characteristics, including the loss of the shelterin component Rap1 (but not the TRF1/TRF2 orthologue, Taz1) from the telomere. We demonstrate that deletion of Rap1 is protective in this context, preventing the growth crisis that is otherwise triggered by degradation of telomeric R-loops in survivors with linear chromosomes. These findings suggest that up-regulation of telomere-engaged TERRA or altered recruitment of shelterin components can support telomerase-independent telomere maintenance.

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Pof8 is a La-related protein and a constitutive component of telomerase in fission yeast

Cited by 30 publications

References 48 publications

Structural basis for recognition of human 7SK long noncoding RNA by the La-related protein Larp7

Structural basis for recognition of human 7SK long noncoding RNA by the La-related protein Larp7

Distribution, organization an evolutionary history of La and LARPs in eukaryotes

RNA-DNA hybrids support recombination-based telomere maintenance in fission yeast

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