title: PinX1, a telomere repeat-binding factor 1 (TRF1)-interacting protein, maintains telomere integrity by modulating TRF1 homeostasis, the process in which human telomerase reverse Transcriptase (hTERT) plays dual roles.
abstract: TRF1, a telomere-binding protein, is important for telomere protection and homeostasis. PinX1 interacts with TRF1, but the physiological consequences of their interaction in telomere protection are not yet understood. Here we investigated PinX1 function on TRF1 stability in HeLa cells. PinX1 overexpression stabilized TRF1, but PinX1 depletion by siRNA led to TRF1 degradation, TRF1 ubiquitination, and less TRF1 telomere association. The depletion also induced DNA damage responses at telomeres and chromosome instability. These telomere dysfunctional phenotypes were in fact due to TRF1 deficiency. We also report that hTERT, a catalytic component of telomerase, plays dual roles in the TRF1 steady state pathway. PinX1-mediated TRF1 stability was not observed in hTERT-negative immortal cells, but was pronounced when hTERT was ectopically expressed in the cells, suggesting that hTERT may be needed in the PinX1-mediated TRF1 stability pathway. Interestingly, the knockdown of both PinX1 and hTERT in HeLa cells stabilized TRF1, suppressed DNA damage response activation, and restored chromosome stability. In summary, our findings suggested that PinX1 may maintain telomere integrity by regulating TRF1 stability and that hTERT may act as both a positive and a negative regulator of TRF1 homeostasis in a PinX1-dependent manner.
authors.affiliation: Department of Pathology, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, 250 Seongsan-ro, Seodaemoon-gu, Seoul 120-752, Korea.
authors.forename: Jeong Eun
authors.initials: JE
authors.lastname: Yoo
authors.affiliation: Department of Pathology, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, 250 Seongsan-ro, Seodaemoon-gu, Seoul 120-752, Korea; Severance Biomedical Science Institute, Yonsei University College of Medicine, 250 Seongsan-ro, Seodaemoon-gu, Seoul 120-752, Korea. Electronic address: young0608@yuhs.ac.
authors.forename: Young Nyun
authors.initials: YN
authors.lastname: Park
authors.affiliation: Department of Obstetrics and Gynecology, Institute of Medical Science, Hanyang University College of Medicine, 222 Wangsimni-ro, Seongdong-gu, Seoul 133-791, Korea. Electronic address: bongoh0401@hanyang.ac.kr.
authors.forename: Bong-Kyeong
authors.initials: BK
authors.lastname: Oh
mesh_terms: D018797:Cell Cycle Proteins; D006367:HeLa Cells; D006801:Humans; D055550:Protein Stability; D019098:Telomerase / Q000235:genetics / Q000502:physiology*; D016615:Telomere / Q000235:genetics / Q000502:physiology*; D059505:Telomere Homeostasis / Q000235:genetics / Q000502:physiology*; D035321:Telomeric Repeat Binding Protein 1 / Q000737:chemistry / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: D018797:Cell Cycle Proteins; C440808:PINX1 protein, human; D035321:Telomeric Repeat Binding Protein 1; D025521:Tumor Suppressor Proteins; C509186:TERT protein, human; D019098:Telomerase
keywords: Chromosomal Instability; DNA Damage Response; TERT; Telomerase; Telomere Deficiency; Telomeres; Telomeric Repeat-binding Factor 1; Tumor Cell Biology; Tumor Suppressor Gene