Our study
is one of basic research directions of the A.N.Belozersky
Institute of Physico-Chemical Biology. The primary subject of interest is tankyrase,
a signaling molecule, which participate in regulation of telomere function and
maintenance.
Telomere is a nucleoprotein complex located
at every end of linear chromosomes of many unicellular and all multicellular
organisms. Chromosome DNA within telomere region is built as a long (no less
than several kb) array of tandem repeats of 6-7 nucleotides. In human telomeres
these are TTAGGG. In aging cells the telomeres can shrink until the cell reach
a condition called cellular senescence. In germ line and stem cells
a specific enzyme telomerase maintains the telomere length, but most
cells of human body have no telomerase activity. Tumor cells can
immortalize themselves, what means that they must gain a property of infinite
proliferation. They escape the cellular senescence mostly using the
telomerase.
The
telomerase activity depends on many factors. For example, TERF proteins block
telomeres and prevent them from binding telomerase. One of them, TERF1,
is a substrate for tankyrase, which can poly(ADP-ribosyl)ate it and remove out
of telomeres. As another substrate tankyrase uses NAD+, it cleaves
NAD+ and synthesizes poly(ADP-ribose) covalently bound to the
protein substrate. Overexpression of TERF1 results in telomere shortening,
while artificial expression of tankyrase with a nuclear localization signal in
telomerase-positive cells can elongate telomeres. Therefore, tankyrase is a
positive regulator of telomerase.
Normally
tankyrase has no nuclear localization signal. It can be transferred into the
nucleus with only its protein substrates. About 90% of the enzyme is located in
cytoplasm, where tankyrase can be activated by mitogen-activated protein kinase
(MAPK). The latter is regulated by polypeptide growth factors and
insulin via Src-like receptors and Ras-MAPK signaling
pathway. Besides TERF1 tankyrase has
some more protein substrates in both nucleus and cytoplasm.
Tankyrase
may also participate in carcinogenesis. We have cloned its isoenzyme 2 as a
candidate tumor antigen according to a scientific program of Ludwig Institute
for Cancer Research. Tankyrase may also take a part in cellular senescence and
immortalization.
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