Authors:	Paez Moscoso, Diego Javier
Title:	Biogenesis of telomerase RNA subunit in schizosaccharomyces pombe
Online publication date:	5-Aug-2021
Year of first publication:	2021
Language:	english
Abstract:	Telomerase is a multi-subunit ribonucleoprotein complex responsible to replenish the missing telomeric DNA sequence during each round of DNA replication. It has two constitutive members: the protein catalytic subunit (TERT) and the telomerase RNA (TER). The TERT subunit is a reverse transcriptase dependent on TER which has the template region for DNA synthesis and the scaffold sequence for its assembly. Dysregulation of telomerase causes human disorders like dyskeratosis congenital, aplastic anemia among others; and reactivation is observed in ~85% of cancers. Since the clinical relevance of telomerase, it is important to develop strategies to manipulate its function. Here, I use the eukaryote Schizosaccharomyces pombe to understand the biogenesis of telomerase. Previous works have identified the S. pombe telomerase RNA (TER1) precursor is bound by the Sm complex. The Sm complex promotes spliceosomal cleavage (splicing reaction albeit skipping the second transesterification step) and trimethyguanosine (TMG) cap formation. TER1 mature form then transitions from Sm to Lsm2-8 (Sm-like) complex, where the latter stabilize the RNA and promotes binding to the catalytic subunit Trt1. I now demonstrate that an efficient sequential binding from Sm to Lsm requires Pof8, a homolog of ciliate telomeres subunit p65/43. Deletion of pof8 results in decreased Lsm2-8 complex loading onto TER1 mature form which causes an important assembly defect and critically short telomeres. The binding of Pof8 to TER1 is enhanced by at least two other members Bmc1, a methyltransferase, and a Thc1, a previously uncharacterized protein. Deletion of Bmc1 and Thc1 resulted in reduce TER1 levels and shorter telomeres. Overall, the findings in this work provide new insights into the stepwise telomerase biogenesis and suggest a possible regulatory mechanism to coordinate the biogenesis of the 5’ and 3’ of TER1 molecules.
DDC:	570 Biowissenschaften 570 Life sciences
Institution:	Johannes Gutenberg-Universität Mainz
Department:	FB 10 Biologie
Place:	Mainz
ROR:	https://ror.org/023b0x485
DOI:	http://doi.org/10.25358/openscience-6221
URN:	urn:nbn:de:hebis:77-openscience-d65a0b53-61c9-4dc1-bed2-a4b58330303e7
Version:	Original work
Publication type:	Dissertation
License:	In Copyright
Information on rights of use:	http://rightsstatements.org/vocab/InC/1.0/
Extent:	IX, 133 Seiten, Diagramme
Appears in collections:	JGU-Publikationen