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TERRA: telomeric repeat-containing RNA.

Luke B, Lingner J - EMBO J. (2009)

Bottom Line: TERRA functions that are emerging suggest important roles in the regulation of telomerase and in orchestrating chromatin remodelling throughout development and cellular differentiation.The accumulation of TERRA at telomeres can also interfere with telomere replication, leading to a sudden loss of telomere tracts.Thus, TERRA may mediate several crucial functions at the telomeres, a region of the genome that had been considered to be transcriptionally silent.

View Article: PubMed Central - PubMed

Affiliation: EPFL-Ecole Polytechnique Fédérale de Lausanne, ISREC-Swiss Institute for Experimental Cancer Research, Lausanne, Switzerland.

ABSTRACT
Telomeres, the physical ends of eukaryotic chromosomes, consist of tandem arrays of short DNA repeats and a large set of specialized proteins. A recent analysis has identified telomeric repeat-containing RNA (TERRA), a large non-coding RNA in animals and fungi, which forms an integral component of telomeric heterochromatin. TERRA transcription occurs at most or all chromosome ends and it is regulated by RNA surveillance factors and in response to changes in telomere length. TERRA functions that are emerging suggest important roles in the regulation of telomerase and in orchestrating chromatin remodelling throughout development and cellular differentiation. The accumulation of TERRA at telomeres can also interfere with telomere replication, leading to a sudden loss of telomere tracts. Such a phenotype can be observed upon impairment of the RNA surveillance machinery or in cells from ICF (Immunodeficiency, Centromeric region instability, Facial anomalies) patients, in which TERRA is upregulated because of DNA methylation defects in the subtelomeric region. Thus, TERRA may mediate several crucial functions at the telomeres, a region of the genome that had been considered to be transcriptionally silent.

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TERRA Biogenesis, telomere association and displacement from telomeres. TERRA Biogenesis (upper panel)—TERRA is an RNAPII-dependent transcript whose transcription initiates within the subtelomeric sequences and proceeds into the telomeric tract. Human TRF1 may promote transcription through the telomere tract through its association with RNAPII. A fraction of TERRA is polyadenylated through the canonical poly(A) polymerase, Pap1. The 5′-end structure that exists on TERRA molecules has not yet been reported. Telomere association (middle panel)—TERRA colocalizes with telomeres as visualized by RNA-FISH experiments on human interphase and metaphase chromosomes. Indirect evidence suggests that at least a portion of TERRA is bound to telomeres through base pairing with telomeric DNA. Undefined RNA–protein interactions or intermolecular G-quadruplex structures (Gquad) may also tether TERRA to telomeric DNA. Telomere removal and degradation (lower panel)—the 5′ to 3′ exonuclease, Rat1, directly degrades TERRA molecules and can itself be found associated with telomeres. Rat1 can degrade its other target RNAs in a co-transcriptional manner (as depicted here), whether TERRA is degraded by Rat1 in a similar manner has yet to be determined. The poly(A) polymerase, Trf4, also contributes to TERRA degradation, although likely as a minor contributor compared with Rat1. The NMD factors, UPF1, SMG1 and EST1A/SMG6, all contribute to TERRA removal from telomeres. Inhibition of any of these factors results in both more and brighter TERRA foci, although overall TERRA levels as assessed by northern blot analysis remain largely unchanged. RNaseH overexpression also reduces cellular TERRA levels when Rat1 function is impaired.
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f1: TERRA Biogenesis, telomere association and displacement from telomeres. TERRA Biogenesis (upper panel)—TERRA is an RNAPII-dependent transcript whose transcription initiates within the subtelomeric sequences and proceeds into the telomeric tract. Human TRF1 may promote transcription through the telomere tract through its association with RNAPII. A fraction of TERRA is polyadenylated through the canonical poly(A) polymerase, Pap1. The 5′-end structure that exists on TERRA molecules has not yet been reported. Telomere association (middle panel)—TERRA colocalizes with telomeres as visualized by RNA-FISH experiments on human interphase and metaphase chromosomes. Indirect evidence suggests that at least a portion of TERRA is bound to telomeres through base pairing with telomeric DNA. Undefined RNA–protein interactions or intermolecular G-quadruplex structures (Gquad) may also tether TERRA to telomeric DNA. Telomere removal and degradation (lower panel)—the 5′ to 3′ exonuclease, Rat1, directly degrades TERRA molecules and can itself be found associated with telomeres. Rat1 can degrade its other target RNAs in a co-transcriptional manner (as depicted here), whether TERRA is degraded by Rat1 in a similar manner has yet to be determined. The poly(A) polymerase, Trf4, also contributes to TERRA degradation, although likely as a minor contributor compared with Rat1. The NMD factors, UPF1, SMG1 and EST1A/SMG6, all contribute to TERRA removal from telomeres. Inhibition of any of these factors results in both more and brighter TERRA foci, although overall TERRA levels as assessed by northern blot analysis remain largely unchanged. RNaseH overexpression also reduces cellular TERRA levels when Rat1 function is impaired.

Mentions: Shelterin is a complex composed of six proteins (TRF1, TRF2, Rap1, TIN2, TPP1 and POT1), which binds to and protects telomeres (Palm and de Lange, 2008). Interestingly, TRF1 can interact with RNAPII as shown through co-immunoprecipitation experiments (Schoeftner and Blasco, 2008). It has been reported that when TRF1 was depleted using small-interfering RNA (siRNA), overall levels of TERRA decreased twofold, which suggests that TRF1 supports TERRA transcription (Schoeftner and Blasco, 2008). It is unlikely, however, that TRF1 acts as a conventional transcriptional activator. First, depletion of TRF1 does not result in a corresponding loss of RNAPII associated with telomeric DNA. Second, TRF1 is restricted to the telomeric tract and likely does not spread into the subtelomere, wherein transcription is presumed to initiate. Finally, the overproduction of TRF1 results in less TERRA production, rather than more, although it should be noted that telomeres shorten in length upon TRF1 overexpression and this may also influence TERRA transcription (Benetti et al, 2008; Schoeftner and Blasco, 2008; Munoz et al, 2009). Overall, these data suggest that TRF1 promotes RNAPII progression through the telomeric tract, but it does not directly influence RNAPII recruitment (see Figure 1, TERRA transcription).


TERRA: telomeric repeat-containing RNA.

Luke B, Lingner J - EMBO J. (2009)

TERRA Biogenesis, telomere association and displacement from telomeres. TERRA Biogenesis (upper panel)—TERRA is an RNAPII-dependent transcript whose transcription initiates within the subtelomeric sequences and proceeds into the telomeric tract. Human TRF1 may promote transcription through the telomere tract through its association with RNAPII. A fraction of TERRA is polyadenylated through the canonical poly(A) polymerase, Pap1. The 5′-end structure that exists on TERRA molecules has not yet been reported. Telomere association (middle panel)—TERRA colocalizes with telomeres as visualized by RNA-FISH experiments on human interphase and metaphase chromosomes. Indirect evidence suggests that at least a portion of TERRA is bound to telomeres through base pairing with telomeric DNA. Undefined RNA–protein interactions or intermolecular G-quadruplex structures (Gquad) may also tether TERRA to telomeric DNA. Telomere removal and degradation (lower panel)—the 5′ to 3′ exonuclease, Rat1, directly degrades TERRA molecules and can itself be found associated with telomeres. Rat1 can degrade its other target RNAs in a co-transcriptional manner (as depicted here), whether TERRA is degraded by Rat1 in a similar manner has yet to be determined. The poly(A) polymerase, Trf4, also contributes to TERRA degradation, although likely as a minor contributor compared with Rat1. The NMD factors, UPF1, SMG1 and EST1A/SMG6, all contribute to TERRA removal from telomeres. Inhibition of any of these factors results in both more and brighter TERRA foci, although overall TERRA levels as assessed by northern blot analysis remain largely unchanged. RNaseH overexpression also reduces cellular TERRA levels when Rat1 function is impaired.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2722245&req=5

f1: TERRA Biogenesis, telomere association and displacement from telomeres. TERRA Biogenesis (upper panel)—TERRA is an RNAPII-dependent transcript whose transcription initiates within the subtelomeric sequences and proceeds into the telomeric tract. Human TRF1 may promote transcription through the telomere tract through its association with RNAPII. A fraction of TERRA is polyadenylated through the canonical poly(A) polymerase, Pap1. The 5′-end structure that exists on TERRA molecules has not yet been reported. Telomere association (middle panel)—TERRA colocalizes with telomeres as visualized by RNA-FISH experiments on human interphase and metaphase chromosomes. Indirect evidence suggests that at least a portion of TERRA is bound to telomeres through base pairing with telomeric DNA. Undefined RNA–protein interactions or intermolecular G-quadruplex structures (Gquad) may also tether TERRA to telomeric DNA. Telomere removal and degradation (lower panel)—the 5′ to 3′ exonuclease, Rat1, directly degrades TERRA molecules and can itself be found associated with telomeres. Rat1 can degrade its other target RNAs in a co-transcriptional manner (as depicted here), whether TERRA is degraded by Rat1 in a similar manner has yet to be determined. The poly(A) polymerase, Trf4, also contributes to TERRA degradation, although likely as a minor contributor compared with Rat1. The NMD factors, UPF1, SMG1 and EST1A/SMG6, all contribute to TERRA removal from telomeres. Inhibition of any of these factors results in both more and brighter TERRA foci, although overall TERRA levels as assessed by northern blot analysis remain largely unchanged. RNaseH overexpression also reduces cellular TERRA levels when Rat1 function is impaired.
Mentions: Shelterin is a complex composed of six proteins (TRF1, TRF2, Rap1, TIN2, TPP1 and POT1), which binds to and protects telomeres (Palm and de Lange, 2008). Interestingly, TRF1 can interact with RNAPII as shown through co-immunoprecipitation experiments (Schoeftner and Blasco, 2008). It has been reported that when TRF1 was depleted using small-interfering RNA (siRNA), overall levels of TERRA decreased twofold, which suggests that TRF1 supports TERRA transcription (Schoeftner and Blasco, 2008). It is unlikely, however, that TRF1 acts as a conventional transcriptional activator. First, depletion of TRF1 does not result in a corresponding loss of RNAPII associated with telomeric DNA. Second, TRF1 is restricted to the telomeric tract and likely does not spread into the subtelomere, wherein transcription is presumed to initiate. Finally, the overproduction of TRF1 results in less TERRA production, rather than more, although it should be noted that telomeres shorten in length upon TRF1 overexpression and this may also influence TERRA transcription (Benetti et al, 2008; Schoeftner and Blasco, 2008; Munoz et al, 2009). Overall, these data suggest that TRF1 promotes RNAPII progression through the telomeric tract, but it does not directly influence RNAPII recruitment (see Figure 1, TERRA transcription).

Bottom Line: TERRA functions that are emerging suggest important roles in the regulation of telomerase and in orchestrating chromatin remodelling throughout development and cellular differentiation.The accumulation of TERRA at telomeres can also interfere with telomere replication, leading to a sudden loss of telomere tracts.Thus, TERRA may mediate several crucial functions at the telomeres, a region of the genome that had been considered to be transcriptionally silent.

View Article: PubMed Central - PubMed

Affiliation: EPFL-Ecole Polytechnique Fédérale de Lausanne, ISREC-Swiss Institute for Experimental Cancer Research, Lausanne, Switzerland.

ABSTRACT
Telomeres, the physical ends of eukaryotic chromosomes, consist of tandem arrays of short DNA repeats and a large set of specialized proteins. A recent analysis has identified telomeric repeat-containing RNA (TERRA), a large non-coding RNA in animals and fungi, which forms an integral component of telomeric heterochromatin. TERRA transcription occurs at most or all chromosome ends and it is regulated by RNA surveillance factors and in response to changes in telomere length. TERRA functions that are emerging suggest important roles in the regulation of telomerase and in orchestrating chromatin remodelling throughout development and cellular differentiation. The accumulation of TERRA at telomeres can also interfere with telomere replication, leading to a sudden loss of telomere tracts. Such a phenotype can be observed upon impairment of the RNA surveillance machinery or in cells from ICF (Immunodeficiency, Centromeric region instability, Facial anomalies) patients, in which TERRA is upregulated because of DNA methylation defects in the subtelomeric region. Thus, TERRA may mediate several crucial functions at the telomeres, a region of the genome that had been considered to be transcriptionally silent.

Show MeSH
Related in: MedlinePlus