Abstract:
:The enzyme telomerase, which elongates chromosome termini, is a critical factor in determining long-term cellular proliferation and tissue renewal. Hence, even small differences in telomerase levels can have substantial consequences for human health. In budding yeast, telomerase consists of the catalytic Est2 protein and two regulatory subunits (Est1 and Est3) in association with the TLC1 RNA, with each of the four subunits essential for in vivo telomerase function. We show here that a hierarchy of assembly and disassembly results in limiting amounts of the quaternary complex late in the cell cycle, following completion of DNA replication. The assembly pathway, which is driven by interaction of the Est3 telomerase subunit with a previously formed Est1-TLC1-Est2 preassembly complex, is highly regulated, involving Est3-binding sites on both Est2 and Est1 as well as an interface on Est3 itself that functions as a toggle switch. Telomerase subsequently disassembles by a mechanistically distinct pathway due to dissociation of the catalytic subunit from the complex in every cell cycle. The balance between the assembly and disassembly pathways, which dictate the levels of the active holoenzyme in the cell, reveals a novel mechanism by which telomerase (and hence telomere homeostasis) is regulated.
journal_name
Genes Devjournal_title
Genes & developmentauthors
Tucey TM,Lundblad Vdoi
10.1101/gad.246256.114subject
Has Abstractpub_date
2014-10-01 00:00:00pages
2077-89issue
19eissn
0890-9369issn
1549-5477pii
gad.246256.114journal_volume
28pub_type
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