PES1 is a critical component of telomerase assembly and regulates cellular senescence

Abstract

Telomerase defers the onset of telomere shortening and cellular senescence by adding telomeric repeat DNA to chromosome ends, and its activation contributes to carcinogenesis. Telomerase minimally consists of the telomerase reverse transcriptase (TERT) and the telomerase RNA (TR). However, how telomerase assembles is largely unknown. Here, we demonstrate that PES1 (Pescadillo), a protein overexpressed in many cancers, forms a complex with TERT and TR through direct interaction with TERT, regulating telomerase activity, telomere length maintenance, and senescence. PES1 does not interact with the previously reported telomerase components Reptin, Pontin, p23, and Hsp90. PES1 facilitates telomerase assembly by promoting direct interaction between TERT and TR without affecting TERT and TR levels. PES1 expression correlates positively with telomerase activity and negatively with senescence in patients with breast cancer. Thus, we identify a previously unknown telomerase complex, and targeting PES1 may open a new avenue for cancer therapy.

Ribosome Biogenesis Alterations in Colorectal Cancer

“…In addition to the role of PES1 and its partner in regulating ribosome biogenesis, an extra-ribosomal role for PES1 was recently described as a direct activator of human telomerase reverse transcriptase (hTERT), resulting in telomere length maintenance and senescence in breast and liver cancer cells [119]. It would be interesting to examine the possible association between the high hTERT activity in CRC [120] and PES1.…”

Telomerase Biogenesis and Activities from the Perspective of Its Direct Interacting Partners

“…Pescadillo homolog (PES1) is the latest nucleolar protein identified as a TERT-binding species. PES1 interaction with TERT is not sensitive to RNase A treatment, and thus, PES1 makes contact with TERT via direct protein-protein binding [ 70 ]. Moreover, since it co-purifies with TERC and dyskerin in the presence of TERT, and its expression correlates positively with telomerase activity both in vitro and in clinical breast cancer samples [ 70 ], PES1 may make contact with the telomerase RNP.…”

“…PES1 interaction with TERT is not sensitive to RNase A treatment, and thus, PES1 makes contact with TERT via direct protein-protein binding [ 70 ]. Moreover, since it co-purifies with TERC and dyskerin in the presence of TERT, and its expression correlates positively with telomerase activity both in vitro and in clinical breast cancer samples [ 70 ], PES1 may make contact with the telomerase RNP. Curiously, PES1 does not co-purify with other known TERT-interacting proteins—HSP90, p23, and fellow nucleolus residents pontin and reptin—in MCF7 cells [ 70 ].…”

“…Moreover, since it co-purifies with TERC and dyskerin in the presence of TERT, and its expression correlates positively with telomerase activity both in vitro and in clinical breast cancer samples [ 70 ], PES1 may make contact with the telomerase RNP. Curiously, PES1 does not co-purify with other known TERT-interacting proteins—HSP90, p23, and fellow nucleolus residents pontin and reptin—in MCF7 cells [ 70 ]. As PES1 binds TERT at similar levels throughout the cell cycle [ 70 ], whereas pontin/reptin association with TERT specifically peaks in S phase [ 67 ], PES1 not immunoprecipitating pontin/reptin may reflect a temporal exclusivity that could not be captured by the PPI method in use.…”

“…Curiously, PES1 does not co-purify with other known TERT-interacting proteins—HSP90, p23, and fellow nucleolus residents pontin and reptin—in MCF7 cells [ 70 ]. As PES1 binds TERT at similar levels throughout the cell cycle [ 70 ], whereas pontin/reptin association with TERT specifically peaks in S phase [ 67 ], PES1 not immunoprecipitating pontin/reptin may reflect a temporal exclusivity that could not be captured by the PPI method in use. In addition to telomerase activity, PES1 expression was found to promote the proliferation of MCF7 cells in a TERT-dependent manner, which also corresponds to c-MYC upregulation [ 70 ].…”