Involvement of SRSF11 in cell cycle-specific recruitment of telomerase to telomeres at nuclear speckles.
Telomerase, a unique ribonucleoprotein complex that contains the telomerase reverse transcriptase (TERT), the telomerase RNA component (TERC) and the TERC-binding protein dyskerin, is required for continued cell proliferation in stem cells and cancer cells. Here we identify SRSF11 as a novel TERC-binding protein that localizes to nuclear speckles, subnuclear structures that are enriched in pre-messenger RNA splicing factors. SRSF11 associates with active telomerase enzyme through an interaction with TERC and directs it to nuclear speckles specifically during S phase of the cell cycle. On the other hand, a subset of telomeres is shown to be constitutively present at nuclear speckles irrespective of cell cycle phase, suggesting that nuclear speckles could be the nuclear sites for telomerase recruitment to telomeres. SRSF11 also associates with telomeres through an interaction with TRF2, which facilitates translocation of telomerase to telomeres. Depletion of SRSF11 prevents telomerase from associating with nuclear speckles and disrupts telomerase recruitment to telomeres, thereby abrogating telomere elongation by telomerase. These findings suggest that SRSF11 acts as a nuclear speckle-targeting factor that is essential for telomerase association with telomeres through the interactions with TERC and TRF2, and provides a potential target for modulating telomerase activity in cancer.
Departments of Systems Biology and Integrated Omics for Biomedical Science, Yonsei University, Seoul 120-749, Korea.
Ji Hoon
JH
Lee
Departments of Systems Biology and Integrated Omics for Biomedical Science, Yonsei University, Seoul 120-749, Korea.
Sun Ah
SA
Jeong
Departments of Systems Biology and Integrated Omics for Biomedical Science, Yonsei University, Seoul 120-749, Korea.
Prabhat
P
Khadka
Departments of Systems Biology and Integrated Omics for Biomedical Science, Yonsei University, Seoul 120-749, Korea.
Juyeong
J
Hong
Departments of Systems Biology and Integrated Omics for Biomedical Science, Yonsei University, Seoul 120-749, Korea topoviro@yonsei.ac.kr.
In Kwon
IK
Chung
D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D022003:Cell Nucleus Structures / Q000201:enzymology* / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D054730:Protein Interaction Domains and Motifs; D012313:RNA / Q000378:metabolism; D000068103:Serine-Arginine Splicing Factors / Q000737:chemistry / Q000378:metabolism*; D019098:Telomerase / Q000737:chemistry / Q000378:metabolism*; D016615:Telomere / Q000201:enzymology*; D059505:Telomere Homeostasis; D035341:Telomeric Repeat Binding Protein 2 / Q000378:metabolism
C000595775:SRSF11 protein, human; D035341:Telomeric Repeat Binding Protein 2; C422952:telomerase RNA; D000068103:Serine-Arginine Splicing Factors; D012313:RNA; D019098:Telomerase