Journal
NATURE COMMUNICATIONS
Volume 9, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-018-05154-z
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Funding
- National Institute of Health [RO1 GM041803]
- start-up funds from the University of Cincinnati
- [T32 CA117846]
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Telomerase elongates the telomeric G-strand to prevent telomere shortening through conventional DNA replication. However, synthesis of the complementary C-strand by DNA polymerase a is also required to maintain telomere length. Polymerase a cannot perform this role without the ssDNA binding complex CST (CTC1-STN1-TEN1). Here we describe the roles of individual CST subunits in telomerase regulation and G-overhang maturation in human colon cancer cells. We show that CTC1-STN1 limits telomerase action to prevent G-overhang overextension. CTC1(-/-)cells exhibit telomeric DNA damage and growth arrest due to overhang elongation whereas TEN1(-/-)cells do not. However, TEN1 is essential for C-strand synthesis and TEN1(-/-)cells exhibit progressive telomere shortening. DNA binding analysis indicates that CTC1-STN1 retains affinity for ssDNA but TEN1 stabilizes binding. We propose CTC1-STN1 binding is sufficient to terminate telomerase action but altered DNA binding dynamics renders CTC1-STN1 unable to properly engage polymerase alpha on the overhang for C-strand synthesis.
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