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Genetics Faculty


Kurt Runge
Associate Professor
Ph.D. Training Faculty
Department of Molecular Genetics
Lerner Research Institute
Cleveland Clinic NE20
9500 Euclid Avenue
Cleveland, Ohio 44195
Tel: (216) 445-9771
Fax: (216) 444-0512
E-mail: kurt.runge@case.edu


About Kurt Runge

Area of general research interest:
* Yeast Telomeres: Formation, Elongation and Suppression of the DNA Damage Checkpoint.
* Control of Life Span and Autophagy through the yeast ortholog of human cdk5.

Current program:
* Suppression of the DNA damage checkpoint by telomeres
* Telomere chromatin structure
* Regulation of lifespan and autophagy by Pef


Research

One goal of our laboratory is to understand what roles telomeres play in chromosome stability and segregation and how this information is communicated to the cell cycle machinery. We approach these problems by forming new telomeres in yeast and monitoring the proteins that are part of yeast telomeric chromatin using yeast genetics and molecular and biochemical approaches such as ChIP and proximity labeling. A second area of focus is the regulation of lifespan. By selecting for long-lived mutants in the fission yeast Schizosaccharomyces pombe, we identified the ortholog of human cdk5, called Pef1, as a regulator of lifespan and autophagy.

Telomeres are the DNA-protein complexes required for the complete replication and stability of chromosome ends. The structure of telemeters in most organisms is a tandem array of short repeated sequences where the strand that makes up the 3' end of the chromosome contains many G residues. In humans and other vertebrates this simple repeat is TTAGGG, in the budding yeast Saccharomyces cerevisiae it is TG1-3 and in the fission yeast Schizosaccharomyces pombe it is predominantly TTACAG1-4. These DNA sequences and the proteins bound to them are the only ones required for telomere function. The number of these repeats, or telomere length, is regulated in both organisms, presumably by balancing the lengthening and shortening activities. In yeasts, the telomere repeat tracts are ~300 bp in length and are bound by specific DNA binding proteins that recognize the double-stranded portion and the 3' single-stranded "tail" at chromosome ends. These proteins then tether as series of interacting proteins that bridge the double-stranded and single-stranded regions and serve to sequester the chromosome end from the DNA damage checkpoint machinery and recruit telomerase. DNA damage checkpoint kinases, that are recruited to DNA double-strand breaks (DSBs) to activate the damage response the halts the cell cycle, are also recruited to telomeres to stimulate their replication without causing arrest (Hector et al., 2007). When the repeats are lost, telomere function is lost and DNA damage kinases that cause cell cycle arrest are recruited (Abdullah et al., 2009, Hector et al., 2012). How telomeres are distinguished from DSBs is a major focus of our work.

To investigate telomere function, we have created the first inducible telomere formation system in S. pombe. This system consists of a short telomere seed (48 bp of repeats) next to a site for a homing endonuclease that does not cut elsewhere in the genome (I-SceI). When transcription for the I-SceI gene is induced, cutting at the site causes loss of the distal sequences and telomere formation. If no telomere repeats are present, the DNA damage checkpoint is activated. However, checkpoint activation is suppressed if telomeres are present even though 50 kb of DNA distal to the cut site is degraded. The suppression of the checkpoint and lack of degradation of the new telomere show that a new telomere is forms immediately after cutting. In contrast, the heterochromatin that is found near telomeres in most organisms takes several generations to completely form (Wang, Eisenstatt, Audry et al., 2018). Consequently, checkpoint suppression is not dependent upon the neighboring chromatin but the telomere repeat chromatin itself. We are currently using this system to identify the proteins and modifying enzymes required for checkpoint suppression.

We have also used S. pombe to probe the regulation of lifespan. After establishing an aging assay that recapitulates the features of mammalian aging (Chen et al. 2011), we performed an unbiased screen that identified a new mutation that extended lifespan (Chen et al., 2013). We identified a cdk-cyclin complex called Pef1-Clg1. Pef1 is an ortholog of mammalian cdk5, and unusual cdk that helps maintain the terminally differentiated state in non-dividing cells. We identified the kinase Cek1 as a downstream effector of Pef1-Clg1, and went on to show that these proteins regulated autophagy. Autophagy is a process by which proteins, lipids and organelles are captured and degraded into components that can be reused by the cell. Besides recycling, autophagy can be used by cells that are starving to survive. Some cancer cells use autophagy as a mode of survival and to evade chemotherapy, so understanding how autophagy is regulated will have impact beyond lifespan regulation. We are currently using proximity labeling along with yeast genetics and genomics to probe the Pef1 regulatory pathways as we prepare for similar experiments in mammalian cells.

We also collaborate with the Berkner lab on the human vitamin K system that is essential for the production of blood coagulation factors, proteins that regulate calcification, cell growth and those of unknown function. Our lab has examined evolutionary conservation of the components of the vitamin K system, including a one protein that was acquired by bacterial pathogen and changed to cause hemorrhagic fever. The combination of evolutionarily conserved sequence and biochemical characterization identified essential residues for protein function. More recently, we have been adapting yeast systems that monitor the interaction of membrane proteins to identify dimerization domains. Mutations that disrupt dimerization will then be tested for effects on biochemical and cell biological function in the Berkner lab.


Selected Publications

Warfarin alters vitamin K metabolism: a surprising mechanism of VKORC1 uncoupling necessitates an additional reductase.
Rishavy MA, Hallgren KW, Wilson L, Singh S, Runge KW, Berkner KL
Blood (2018);131(25):2826-2835
See PubMed abstract

Identification of a lifespan extending mutation in the Schizosaccharomyces pombe cyclin gene clg1+ by direct selection of long-lived mutants.
Chen BR, Li Y, Eisenstatt JR, Runge KW
PLoS One (2013);8(7):e69084
See PubMed abstract

Mec1p associates with functionally compromised telomeres.
Hector RE, Ray A, Chen BR, Shtofman R, Berkner KL, Runge KW
Chromosoma (2012);121(3):277-90
See PubMed abstract

A two-step model for senescence triggered by a single critically short telomere.
Abdallah P, Luciano P, Runge KW, Lisby M, Géli V, Gilson E, Teixeira MT
Nat Cell Biol (2009);11(8):988-93
See PubMed abstract

Tel1p preferentially associates with short telomeres to stimulate their elongation.
Hector RE, Shtofman RL, Ray A, Chen BR, Nyun T, Berkner KL, Runge KW
Mol Cell (2007);27(5):851-8
See PubMed abstract

A new model for vitamin K-dependent carboxylation: the catalytic base that deprotonates vitamin K hydroquinone is not Cys but an activated amine.
Rishavy MA, Pudota BN, Hallgren KW, Qian W, Yakubenko AV, Song JH, Runge KW, Berkner KL.
Proc Natl Acad Sci U S A. (2004);101(38):13732-7
See PubMed abstract

Sir3p phosphorylation by the Slt2p pathway effects redistribution of silencing function and shortened lifespan.
Ray A, Hector RE, Roy N, Song JH, Berkner KL, Runge KW.
Nat Genet. (2003);33(4):522-6
See PubMed abstract

Yeast telomerase appears to frequently copy the entire template in vivo.
Ray A, Runge KW.
Nucleic Acids Res. (2001);29(11):2382-94.
See PubMed abstract

Two paralogs involved in transcriptional silencing that antagonistically control yeast life span.
Roy N, Runge KW.
Curr Biol. (2000);10(2):111-4
See PubMed abstract

Varying the number of telomere-bound proteins does not alter telomere length in tel1Delta cells.
Ray A, Runge KW.
Proc Natl Acad Sci U S A. (1999);96(26):15044-9.
See PubMed abstract

Tel2p, a regulator of yeast telomeric length in vivo, binds to single-stranded telomeric DNA in vitro.
Kota RS, Runge KW.
Chromosoma. (1999);108(5):278-90
See PubMed abstract

The ZDS1 and ZDS2 proteins require the Sir3p component of yeast silent chromatin to enhance the stability of short linear centromeric plasmids.
Roy N, Runge KW.
Chromosoma. (1999);108(3):146-61.
See PubMed abstract

The yeast telomere length counting machinery is sensitive to sequences at the telomere-nontelomere junction.
Ray A, Runge KW.
Mol Cell Biol. (1999);19(1):31-45.
See PubMed abstract