期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 289, 期 10, 页码 6886-6898出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M113.506006
关键词
DNA Damage Response; Telomerase; Telomeres; Tumor Cell Biology; Tumor Suppressor Gene; DNA Damage Response; TERT; Chromosomal Instability; Telomere Deficiency; Telomeric Repeat-binding Factor 1
资金
- National Research Foundation of Korea [2013R1A2A2A05005990, 2012M3A9B6055350, 2011-0030086, 2010-0008254, 2011-0015638]
- Ministry of Education, Science and Technology
- National Research Foundation of Korea [2011-0015638, 2010-0008254, 2012M3A9B6055350, 2013R1A2A2A05005990, 2011-0030086] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Background: PinX1 interacts with TRF1 and hTERT, but the significance of the physical association is not fully understood. Results: PinX1 is involved in chromosome stability by regulating TRF1 protein stability, and the function of PinX1 is linked to hTERT. Conclusion: PinX1 is functionally connected with hTERT to maintain TRF1 stability. Significance: These findings suggest that a TRF1 turnover mechanism is linked to telomerase. 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.
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