Proper maintenance of telomere structure is crucial for stable inheritance of the genome. Various checkpoint and DNA repair proteins, including evolutionarily highly conserved checkpoint kinases Tel1 (ATM) and Rad3 (ATR), play important roles in stable maintenance of telomeres. However, no clear mechanistic roles for various checkpoint and DNA repair proteins in telomere maintenance have been established. Major goal of our research is to understand how checkpoint and DNA repair proteins contribute to telomere maintenance. The current proposal will utilize fission yeast Schizosaccharomyces pombe as a model system. Highly conserved DNA damage responses and telomere maintenance mechanisms between fission yeast and humans should be helpful in extrapolating our findings to build testable models for human cells. Deregulation of telomere maintenance mechanisms has been found to be a key event in tumorigenesis, thus mechanistic insights on how various proteins collaborate to generate functional telomeres are first needed to devise effective methods for preventing tumorigenesis. In order to be stably maintained, telomeres must fulfill two major functions. First, telomeres must protect telomeric DNA ends from fusions and degradation. Second, telomeres must provide access to telomerase to prevent loss of telomeric DNA after DNA replication. Thus, telomeres must undergo dynamic switches from the highly protected state to the more accessible state that allows recruitment of telomerase. We hypothesize that checkpoint and DNA repair proteins are recruited to telomeres in a cell cycle-regulated manner to trigger appropriate changes in telomere structure and telomere protein composition. This model will be directly tested in Aim 1. Additionally, newly developed fission yeast reporter strains will be utilized to search for potential telomere targets of Rad3 and Tel1 kinases in Aim 2. Our preliminary studies with MRN (Mre11-Rad50-Nbs1) complex mutants have suggested that recruitment of Tel1 to telomeres does not require Tel1-MRN interaction unlike recruitment of Tel1 to other DNA breaks. Therefore, attempts will be made in Aim 3 to understand the mechanistic basis for the MRN-independent recruitment of Tel1 to telomeres.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM078253-04
Application #
7661545
Study Section
Molecular Genetics C Study Section (MGC)
Program Officer
Carter, Anthony D
Project Start
2006-08-01
Project End
2011-07-31
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
4
Fiscal Year
2009
Total Cost
$263,322
Indirect Cost
Name
University of Illinois at Chicago
Department
Biochemistry
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Matmati, Samah; Vaurs, Mélina; Escandell, José M et al. (2018) The fission yeast Stn1-Ten1 complex limits telomerase activity via its SUMO-interacting motif and promotes telomeres replication. Sci Adv 4:eaar2740
Mennie, Amanda K; Moser, Bettina A; Nakamura, Toru M (2018) LARP7-like protein Pof8 regulates telomerase assembly and poly(A)+TERRA expression in fission yeast. Nat Commun 9:586
Nie, Minghua; Moser, Bettina A; Nakamura, Toru M et al. (2017) SUMO-targeted ubiquitin ligase activity can either suppress or promote genome instability, depending on the nature of the DNA lesion. PLoS Genet 13:e1006776
Gadaleta, Mariana C; Das, Mukund M; Tanizawa, Hideki et al. (2016) Swi1Timeless Prevents Repeat Instability at Fission Yeast Telomeres. PLoS Genet 12:e1005943
Moser, Bettina A; Raguimova, Olga N; Nakamura, Toru M (2015) Ccq1-Tpz1TPP1 interaction facilitates telomerase and SHREC association with telomeres in fission yeast. Mol Biol Cell 26:3857-66
Audry, Julien; Maestroni, Laetitia; Delagoutte, Emmanuelle et al. (2015) RPA prevents G-rich structure formation at lagging-strand telomeres to allow maintenance of chromosome ends. EMBO J 34:1942-58
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
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
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

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