Unveiling PES1’s role in Telomerase assembly and regulation of cellular aging

PES1 regulates cellular senescence and is an important component in telomerase assembly

Telomerase delays the onset of telomere senescence and cell senescence, and its activation is linked to cancer. Telomerase is composed of a telomerase reverse transcriptionase (TERT), and telomerase transcript (TR). It is not known how telomerase is assembled. We show that PES1(Pescadillo), which is overexpressed by many cancers forms a complex TERT and TR via direct interaction with TERT. This complex regulates telomerase, telomere maintenance and senescence. PES1 is not able to interact with previously reported components of telomerase, such as Reptin Pontin p23 and Hsp90. PES1 promotes telomerase assembling by promoting the direct interaction between TR and TERT without affecting TR and TERT levels. PES1 expression is positively correlated with telomerase activities and negatively correlated with senescence among breast cancer patients. We have identified a previously unidentified telomerase, and PES1 targeting may be a novel cancer treatment.

Telomerase, a ribonucleoprotein enzyme (RNP), adds telomeric DNA repeats to the ends of chromosomes (1-3). This prevents the progressive shortening telomeres that is caused by the DNA replication machinery failing to duplicate the end of every chromosome. Cells that have telomeres shorter than a certain amount enter replicative senescence, or alternatively undergo apoptosis. This is a powerful tumor suppressing mechanism. Telomerase is essential for de novo DNA synthesis of telomeric repeats and telomere preservation. It is expressed by approximately 90% of cancerous cells, but is not detected in most normal somatic cells. Telomerase has been identified as a factor that distinguishes cancerous cells from normal ones. It is also a therapeutic target.

Telomerase is composed of telomerase reverse transcriptionase, or TERT. In vitro assembly was demonstrated by combining purified RNA with TERT synthesized from rabbit reticulocytes extracts (7-9). A few accessory protein have been identified that associate with the active RNP complex of telomerase. Hsp90 and p23 are molecular chaperones that bind human TERT. Chemical inhibition of Hsp90 reduces telomerase activities (10, 11). It is difficult to determine whether Hsp90 assembly is necessary for active telomerase because chemical inhibition can have a pleiotropic or indirect effect. The adenosine Triphosphatases Reptin, and Pontin (12) facilitate the assembly of human TR and hTERT to catalytically-active telomerase. Pontin knockdown reduces both telomerase levels and activity.

Source:
https://advances.sciencemag.org/content/5/5/eaav1090

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