Jan Karlseder
   HOME

TheInfoList



OR:

Jan Karlseder (born September 28, 1968, in
Innsbruck Innsbruck (; ) is the capital of Tyrol (federal state), Tyrol and the List of cities and towns in Austria, fifth-largest city in Austria. On the Inn (river), River Inn, at its junction with the Wipptal, Wipp Valley, which provides access to the ...
) an Austrian molecular biologist, is the Chief Science Officer and a Senior Vice President at the Salk Institute for Biological Studies. He is also a
professor Professor (commonly abbreviated as Prof.) is an Academy, academic rank at university, universities and other tertiary education, post-secondary education and research institutions in most countries. Literally, ''professor'' derives from Latin ...
in the Molecular and Cellular Biology Laboratory, the Director of the ''Paul F. Glenn Center for Biology of Aging Research'' and the holder of the
Donald Donald is a Scottish masculine given name. It is derived from the Gaelic name ''Dòmhnall''.. This comes from the Proto-Celtic *''Dumno-ualos'' ("world-ruler" or "world-wielder"). The final -''d'' in ''Donald'' is partly derived from a misinter ...
and Darlene Shiley Chair at the
Salk Institute for Biological Studies The Salk Institute for Biological Studies is a scientific research institute in the La Jolla community of San Diego, California. The independent, non-profit institute was founded in 1960 by Jonas Salk, the developer of the polio vaccine; among th ...
.


Career

Karlseder obtained both his M.Sc. and his Ph.D. at the
University of Vienna The University of Vienna (, ) is a public university, public research university in Vienna, Austria. Founded by Rudolf IV, Duke of Austria, Duke Rudolph IV in 1365, it is the oldest university in the German-speaking world and among the largest ...
. In 1996, he joined the Laboratory of Titia de Lange at
Rockefeller University The Rockefeller University is a Private university, private Medical research, biomedical Research university, research and graduate-only university in New York City, New York. It focuses primarily on the biological and medical sciences and pro ...
in New York City for postdoctoral training. He became a faculty member at the
Salk Institute for Biological Studies The Salk Institute for Biological Studies is a scientific research institute in the La Jolla community of San Diego, California. The independent, non-profit institute was founded in 1960 by Jonas Salk, the developer of the polio vaccine; among th ...
in 2002.


Research

Karlseder discovered that
telomere A telomere (; ) is a region of repetitive nucleotide sequences associated with specialized proteins at the ends of linear chromosomes (see #Sequences, Sequences). Telomeres are a widespread genetic feature most commonly found in eukaryotes. In ...
dysfunction plays a role in
Werner Syndrome Werner syndrome (WS) or Werner's syndrome, also known as "adult progeria",James, William; Berger, Timothy; Elston, Dirk (2005). ''Andrews' Diseases of the Skin: Clinical Dermatology''. (10th ed.). Saunders. . is a rare autosomal recessive disord ...
, a premature aging disease that is associated with early onset of cancer.
WRN helicase Werner syndrome ATP-dependent helicase, also known as DNA helicase, RecQ-like type 3, is an enzyme that in humans is encoded by the ''WRN'' gene. WRN is a member of the RecQ Helicase family. Helicase enzymes generally unwind and separate double-s ...
, which is mutated in Werner Syndrome patients, is required for efficient replication of the telomeric G-strand. Without WRN,
lagging strand In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all living organisms, acting as the most essential part of biological inheritance ...
replication frequently stalls at telomeres, leading to loss of one of the sister telomeres during replication and
cell division Cell division is the process by which a parent cell (biology), cell divides into two daughter cells. Cell division usually occurs as part of a larger cell cycle in which the cell grows and replicates its chromosome(s) before dividing. In eukar ...
. This telomere loss in turn can lead to telomere end-to-end fusions, fusion-bridge-breakage cycles and
genome instability Genome instability (also genetic instability or genomic instability) refers to a high frequency of mutations within the genome of a cellular lineage. These mutations can include changes in nucleic acid sequences, chromosomal rearrangements or ...
, which is responsible for the heightened cancer incidence in individuals with Werner Syndrome. He went on to show that following
DNA replication In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all life, living organisms, acting as the most essential part of heredity, biolog ...
telomeres are recognized by the intracellular
DNA damage DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. A weakened capacity for DNA repair is a risk factor for the development of cancer. DNA is constantly modified ...
machinery. This seemingly paradoxical event turned out to be essential to recruit the machinery that establishes protection at
chromosome A chromosome is a package of DNA containing part or all of the genetic material of an organism. In most chromosomes, the very long thin DNA fibers are coated with nucleosome-forming packaging proteins; in eukaryotic cells, the most import ...
ends, where the
homologous recombination Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids (usually DNA as in Cell (biology), cellular organi ...
machinery acts to form a structure that is resistant to
nuclease In biochemistry, a nuclease (also archaically known as nucleodepolymerase or polynucleotidase) is an enzyme capable of cleaving the phosphodiester bonds that link nucleotides together to form nucleic acids. Nucleases variously affect single and ...
s and damage repair. Karlseder’s work on DNA repair pathway choice led to the discovery of the microprotein CYREN, which inhibits error prone
non-homologous end-joining Non-homologous end joining (NHEJ) is a pathway that repairs double-strand breaks in DNA. It is called "non-homologous" because the break ends are directly ligated without the need for a homologous template, in contrast to homology directed repair ...
during S and
G2 phase G2 phase, Gap 2 phase, or Growth 2 phase, is the third subphase of interphase in the cell cycle directly preceding mitosis. It follows the successful completion of S phase, during which the cell’s DNA is replicated. G2 phase ends with the o ...
s of the
cell cycle The cell cycle, or cell-division cycle, is the sequential series of events that take place in a cell (biology), cell that causes it to divide into two daughter cells. These events include the growth of the cell, duplication of its DNA (DNA re ...
, thereby promoting DNA break repair by the error free
homologous recombination Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids (usually DNA as in Cell (biology), cellular organi ...
machinery. Karlseder discovered that mitotic arrest leads to telomere deprotection, which triggers a stress response that leads to the  death of cells that cannot complete
mitosis Mitosis () is a part of the cell cycle in eukaryote, eukaryotic cells in which replicated chromosomes are separated into two new Cell nucleus, nuclei. Cell division by mitosis is an equational division which gives rise to genetically identic ...
. He demonstrated that this process is at play during replicative crisis, where fused telomeres trigger mitotic arrest and in turn
cell death Cell death is the event of a biological cell ceasing to carry out its functions. This may be the result of the natural process of old cells dying and being replaced by new ones, as in programmed cell death, or may result from factors such as di ...
within one or two cell cycles. Karlseder’s work on recombination-based telomere maintenance (ALT) revealed that constitutive damage signals from shortening telomeres down-regulate
histone In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei and in most Archaeal phyla. They act as spools around which DNA winds to create structural units called nucleosomes ...
synthesis, which leads to changes in
nucleosome A nucleosome is the basic structural unit of DNA packaging in eukaryotes. The structure of a nucleosome consists of a segment of DNA wound around eight histone, histone proteins and resembles thread wrapped around a bobbin, spool. The nucleosome ...
availability and histone chaperone expression. This led to the discovery that
replication fork In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all living organisms, acting as the most essential part of biological inheritanc ...
stalling at telomeres plays a major role in the activation of ALT. He found that cell death in replicative crisis is executed by the
autophagy Autophagy (or autophagocytosis; from the Greek language, Greek , , meaning "self-devouring" and , , meaning "hollow") is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-depe ...
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. Karlseder’s work on connecting telomere dysfunction with
inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...
and
cell death Cell death is the event of a biological cell ceasing to carry out its functions. This may be the result of the natural process of old cells dying and being replaced by new ones, as in programmed cell death, or may result from factors such as di ...
during replicative crisis identified
ZBP1 Z-DNA-binding protein 1, also known as DNA-dependent activator of IFN-regulatory factors (DAI) and DLM-1, is a protein that in humans is encoded by the ''ZBP1'' gene. ZBP1 is also an abbreviation for chicken or rat β-actin zipcode-binding prote ...
as novel regulator of the innate RNA sensing machinery. He discovered that cells in replicative crisis use the telomeric transcript TERRA as messenger to sense critically short telomeres. TERRA associates with the innate RNA sensor ZBP1, which in turn forms filaments at the mitochondrial outer membrane, where it activates its adaptor MAVS, resulting in an amplification of an
interferon type 1 The type-I interferons (IFN) are cytokines which play essential roles in inflammation, immunoregulation, tumor cells recognition, and T cell, T-cell responses. In the human genome, a cluster of thirteen functional IFN genes is located at the 9p2 ...
inflammation response. Karlseder thereby discovered a novel tumor suppressive pathway, which removes aged cells with critically short telomeres, which would be prone to cancerous transformation.


References

{{DEFAULTSORT:Karlseder, Jan Austrian molecular biologists 21st-century Austrian biologists University of Vienna alumni 1968 births Living people Salk Institute for Biological Studies people Scientists from Innsbruck