Kurt Runge Laboratory

Research

Our lab primarily studies how telomeres differ from DNA breaks, and how the cell division kinase Pef1 (ortholog of human cdk5) regulates autophagy and cell lifespan using the yeast Schizosaccharomyces pombe, with some work in tissue culture cells.  We also collaborate with Dr. Kathleen Berkner’s lab in Cardiovascular and Metabolic Sciences in study the vitamin K-dependent carboxylation system in humans and other metazoans. 

Telomeres, the physical ends of chromosomes, differ from double-strand DNA breaks (DSBs) as they do not activate DNA damage checkpoints that arrest the cell cycle.  Our lab developed a novel, inducible telomere formation system for the fission yeast S. pombe, and used it to monitor the kinetics of telomere forma tion and the accompanying chromatin modifications.  We found that the telomere functions that distinguish these ends from DSBs are manifested as soon as the telomere is formed, while the spread of heterochromatin from the telomere that represses gene transcription takes many generations to form.  This difference can be visualized by placing a gene that causes cells to turn red when it is repressed (ade6+) at different distances from the telomere.  When cells are plated onto medium that induces telomere formation, the cells near the center of the colony are white but subsequent generations turn red as spreading heterochromatin extinguishes ade6+ expression. We are extending this system to explore the differences between the forming telomere and a DSB.

Yeast Telomere Formation

Telomere repeats (black triangles) next to an induced DNA break (red triangle) immediately form a functional telomere while distal DNA is degraded.

Heterochromatin spreads slowly from the newly formed telomere.

We discovered that the cdk Pef1 regulates S. pombe lifespan in an unbiased genetic screen for long-lived mutants.  Pef1 is an ortholog of human cdk5, and we found that Pef1, like cdk5, regulates the level of autophagy, a cellular “recycling process” that digests cellular components to component parts for further use.  We identified S. pombe Clg1 as the relevant Pef1 cyclin, and the MAST-like kinase Cek1 as the downstream effector in the Clg1-Pef1-Cek1 pathway that regulates lifespan.  We are leveraging the unique features of S. pombe to determine which nutritional starvations induce autophagy and how the Clg1-Pef1-Cek1 pathway controls this induction.  We have also adapted the APEX2-based proximity labeling approach to S. pombe to biotinylate proteins near Pef1.  Comparing cells grown under conditions that induce or do not induce autophagy will reveal proteins and pathways that Pef1 may control for subsequent study.

The Clg1-Pef1-Cek1 pathway controls lifespan and autophagy by unknown mechanisms.

Proximity labeling identifies proteins near Pef1 in vivo.

Selected Publications

1.

Telomere-binding proteins Taz1 and Rap1 regulate DSB repair and suppress gross chromosomal rearrangements in fission yeast.

Irie H, Yamamoto I, Tarumoto Y, Tashiro S, Runge KW, Ishikawa F.

PLoS Genet. 2019 Aug 27;15(8):e1008335. doi: 10.1371/journal.pgen.1008335. eCollection 2019 Aug.

PMID: 31454352 Free PMC article.

2.

The inhibition of checkpoint activation by telomeres does not involve exclusion of dimethylation of histone H4 lysine 20 (H4K20me2).

Audry J, Wang J, Eisenstatt JR, Berkner KL, Runge KW.

F1000Res. 2018 Jul 9;7:1027. doi: 10.12688/f1000research.15166.2. eCollection 2018.

PMID: 30498568 Free PMC article.

3.

A Heterochromatin Domain Forms Gradually at a New Telomere and Is Dynamic at Stable Telomeres.

Wang J, Eisenstatt JR, Audry J, Cornelius K, Shaughnessy M, Berkner KL, Runge KW.

Mol Cell Biol. 2018 Jul 16;38(15):e00393-17. doi: 10.1128/MCB.00393-17. Print 2018 Aug 1.

PMID: 29784772 Free PMC article.

4.

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 Jun 21;131(25):2826-2835. doi: 10.1182/blood-2017-09-804666. Epub 2018 Mar 28.

PMID: 29592891 Free PMC article.

5.

Nonhomologous End-Joining with Minimal Sequence Loss Is Promoted by the Mre11-Rad50-Nbs1-Ctp1 Complex in Schizosaccharomyces pombe.

Li Y, Wang J, Zhou G, Lajeunesse M, Le N, Stawicki BN, Corcino YL, Berkner KL, Runge KW.

Genetics. 2017 May;206(1):481-496. doi: 10.1534/genetics.117.200972. Epub 2017 Mar 14.

PMID: 28292918 Free PMC article.

6.

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 Jul 9;8(7):e69084. doi: 10.1371/journal.pone.0069084. Print 2013.

PMID: 23874875 Free PMC article.

7.

Mec1p associates with functionally compromised telomeres.

Hector RE, Ray A, Chen BR, Shtofman R, Berkner KL, Runge KW.

Chromosoma. 2012 Jun;121(3):277-90. doi: 10.1007/s00412-011-0359-0.

PMID: 22289863 Free PMC article.

8.

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 Aug;11(8):988-93. doi: 10.1038/ncb1911. Epub 2009 Jul 13.

PMID: 19597486 Free PMC article.

9.

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 Sep 7;27(5):851-8. doi: 10.1016/j.molcel.2007.08.007.

PMID: 17803948

10.

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 Apr;33(4):522-6. doi: 10.1038/ng1132. Epub 2003 Mar 17.

PMID: 12640455