Jan Karlseder

Jan Karlseder (born September 28, 1968, in Innsbruck) is an Austrian molecular biologist, a professor in the Molecular and Cellular Biology Laboratory, the Director of the Paul F. Glenn Center for Biology of Aging Research[1] and the holder of the Donald and Darlene Shiley Chair at the Salk Institute for Biological Studies.

Career

Karlseder obtained both his M.Sc. and his Ph.D. at the University of Vienna. In 1996, he joined the Laboratory of Titia de Lange at Rockefeller University in New York City for postdoctoral training. He became a faculty member at the Salk Institute for Biological Studies in 2002.

Research

Karlseder discovered that telomere dysfunction plays a role in Werner Syndrome, a premature aging disease that is associated with early onset of cancer. WRN helicase, which is mutated in Werner Syndrome patients, is required for efficient replication of the telomeric G-strand.[2] Without WRN, lagging strand replication frequently stalls at telomeres, leading to loss of one of the sister telomeres during replication and cell division. This telomere loss in turn can lead to telomere end-to-end fusions, fusion-bridge-breakage cycles and genome instability, which is responsible for the heightened cancer incidence in individuals with Werner Syndrome.[3] He went on to show that following DNA replication telomeres are recognized by the intracellular DNA damage machinery.[4] This seemingly paradoxical event turned out to be essential to recruit the machinery that establishes protection at chromosome ends, where the homologous recombination machinery acts to form a structure that is resistant to nucleases and damage repair. [5]

Karlseder’s work on recombination-based telomere maintenance (ALT) revealed that constitutive damage signals from shortening telomeres down-regulate histone synthesis, which leads to changes in nucleosome availability and histone chaperone expression.[6] This led to the discovery that replication fork stalling at telomeres plays a major role in the activation of ALT.[7]

He found that cell death in replicative crisis is executed by the autophagy machinery. Autophagy suppression allowed cells to bypass crisis and continue to proliferate with critically short telomeres, accumulating high levels of genome instability, pointing at autophagy as a potent tumor suppressor during the earliest stages of cancer initiation.[8]

References
  1. "Glenn Foundation for Medical Research Glenn Center for Research on Aging". glennfoundation.org. Retrieved 2021-01-20.
  2. Crabbe, Laure; Verdun, Ramiro E.; Haggblom, Candy I.; Karlseder, Jan (2004-12-10). "Defective Telomere Lagging Strand Synthesis in Cells Lacking WRN Helicase Activity". Science. 306 (5703): 1951–1953. Bibcode:2004Sci...306.1951C. doi:10.1126/science.1103619. ISSN 0036-8075. PMID 15591207. S2CID 32602639.
  3. Crabbe, L.; Jauch, A.; Naeger, C. M.; Holtgreve-Grez, H.; Karlseder, J. (2007-02-06). "Telomere dysfunction as a cause of genomic instability in Werner syndrome". Proceedings of the National Academy of Sciences. 104 (7): 2205–2210. Bibcode:2007PNAS..104.2205C. doi:10.1073/pnas.0609410104. ISSN 0027-8424. PMC 1794219. PMID 17284601.
  4. Verdun, Ramiro E.; Crabbe, Laure; Haggblom, Candy; Karlseder, Jan (2005). "Functional Human Telomeres Are Recognized as DNA Damage in G2 of the Cell Cycle". Molecular Cell. 20 (4): 551–561. doi:10.1016/j.molcel.2005.09.024. PMID 16307919.
  5. Verdun, Ramiro E.; Karlseder, Jan (2006). "The DNA Damage Machinery and Homologous Recombination Pathway Act Consecutively to Protect Human Telomeres". Cell. 127 (4): 709–720. doi:10.1016/j.cell.2006.09.034. PMID 17110331. S2CID 16644043.
  6. O'Sullivan, Roderick J.; Kubicek, Stefan; Schreiber, Stuart L.; Karlseder, Jan (October 2010). "Reduced histone biosynthesis and chromatin changes arising from a damage signal at telomeres". Nature Structural & Molecular Biology. 17 (10): 1218–1225. doi:10.1038/nsmb.1897. ISSN 1545-9985. PMC 2951278. PMID 20890289.
  7. O'Sullivan, Roderick J.; Arnoult, Nausica; Lackner, Daniel H.; Oganesian, Liana; Haggblom, Candy; Corpet, Armelle; Almouzni, Genevieve; Karlseder, Jan (February 2014). "Rapid induction of alternative lengthening of telomeres by depletion of the histone chaperone ASF1". Nature Structural & Molecular Biology. 21 (2): 167–174. doi:10.1038/nsmb.2754. ISSN 1545-9985. PMC 3946341. PMID 24413054.
  8. Nassour, Joe; Radford, Robert; Correia, Adriana; Fusté, Javier Miralles; Schoell, Brigitte; Jauch, Anna; Shaw, Reuben J.; Karlseder, Jan (January 2019). "Autophagic cell death restricts chromosomal instability during replicative crisis". Nature. 565 (7741): 659–663. Bibcode:2019Natur.565..659N. doi:10.1038/s41586-019-0885-0. ISSN 1476-4687. PMC 6557118. PMID 30675059.
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