Stable maintenance of telomeres is critical to preserve genomic integrity and prevent accumulation of undesired mutations that might lead to various human diseases. In mammalian cells, GT-rich telomeric repeats are bound by the six-protein "shelterin" complex (composed of TRF1, TRF2, RAP1, TIN2, TPP1 and POT1) and extended by the specialized reverse transcriptase known as telomerase. The shelterin complex is essential to prevent DNA repair proteins from fusing telomeres and DNA damage checkpoint proteins from causing permanent cell cycle arrest. On the other hand, these DNA damage response factors must gain at least transient access to telomeres, since they play critical roles in both telomere protection and telomerase recruitment. Thus, the proper maintenance of telomeres involves dynamic changes between "closed" (protected) and "open" (accessible) states. However, it is still not fully understood how individual subunits of the shelterin complex are regulated to ensure proper transition of the telomere status. In addition, the critical telomere target(s) for DNA damage checkpoint proteins remain to be established. Therefore, we propose to utilize fission yeast Schizosaccharomyces pombe as a model system to investigate how telomere maintenance is ensured by collaboration among telomere specific factors and DNA damage response factors. Fission yeast should serve as an attractive model system for mammalian telomere maintenance mechanism, since the shelterin complex, telomerase components, and DNA damage response proteins are highly conserved between fission yeast and mammals.

Public Health Relevance

Stable maintenance of telomeres is critical to preserve genomic integrity and prevent accumulation of undesired mutations that might lead to tumor formation. The overall goals of this proposal are to provide a detailed knowledge of the mechanisms that allow the telomere protection complex shelterin and DNA damage checkpoint sensor kinases Rad3 (ATR) and Tel1 (ATM) to work in concert to achieve stable telomere maintenance in fission yeast Schizosaccharomyces pombe. Since proteins involved in telomere maintenance and DNA damage responses are highly conserved between fission yeast and humans, we expect our findings to have major impacts in guiding future studies of human telomere regulations.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01GM078253-09
Application #
8708888
Study Section
Molecular Genetics C Study Section (MGC)
Program Officer
Carter, Anthony D
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Biochemistry
Type
Schools of Medicine
DUNS #
City
Chicago
State
IL
Country
United States
Zip Code
60612
Harland, Jennifer L; Chang, Ya-Ting; Moser, Bettina A et al. (2014) Tpz1-Ccq1 and Tpz1-Poz1 interactions within fission yeast shelterin modulate Ccq1 Thr93 phosphorylation and telomerase recruitment. PLoS Genet 10:e1004708
Miyagawa, Keisuke; Low, Ross S; Santosa, Venny et al. (2014) SUMOylation regulates telomere length by targeting the shelterin subunit Tpz1(Tpp1) to modulate shelterin-Stn1 interaction in fission yeast. Proc Natl Acad Sci U S A 111:5950-5
Moser, Bettina A; Chang, Ya-Ting; Nakamura, Toru M (2014) Telomere regulation during the cell cycle in fission yeast. Methods Mol Biol 1170:411-24
Chang, Ya-Ting; Moser, Bettina A; Nakamura, Toru M (2013) Fission yeast shelterin regulates DNA polymerases and Rad3(ATR) kinase to limit telomere extension. PLoS Genet 9:e1003936
Moser, Bettina A; Chang, Ya-Ting; Kosti, Jorgena et al. (2011) Tel1ATM and Rad3ATR kinases promote Ccq1-Est1 interaction to maintain telomeres in fission yeast. Nat Struct Mol Biol 18:1408-13
Khair, Lyne; Subramanian, Lakxmi; Moser, Bettina A et al. (2010) Roles of heterochromatin and telomere proteins in regulation of fission yeast telomere recombination and telomerase recruitment. J Biol Chem 285:5327-37
Khair, Lyne; Chang, Ya-Ting; Subramanian, Lakxmi et al. (2010) Roles of the checkpoint sensor clamp Rad9-Rad1-Hus1 (911)-complex and the clamp loaders Rad17-RFC and Ctf18-RFC in Schizosaccharomyces pombe telomere maintenance. Cell Cycle 9:2237-48
Subramanian, Lakxmi; Nakamura, Toru M (2010) A kinase-independent role for the Rad3(ATR)-Rad26(ATRIP) complex in recruitment of Tel1(ATM) to telomeres in fission yeast. PLoS Genet 6:e1000839
Carneiro, Tiago; Khair, Lyne; Reis, Clara C et al. (2010) Telomeres avoid end detection by severing the checkpoint signal transduction pathway. Nature 467:228-32
Subramanian, Lakxmi; Nakamura, Toru M (2010) To fuse or not to fuse: how do checkpoint and DNA repair proteins maintain telomeres? Front Biosci (Landmark Ed) 15:1105-18

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