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JAK-STAT signal path

The JAK-STAT signal transmission is conserved evolutionarily in vertebrates and some other multicellular organisms. The combination of receptor-activated kinases and transcription factors make this signal cascade one of the central cellular regulatory pathways.

In vertebrates, the JAK-STAT signal transmission is based on a network of protein kinases and transcription factors with which signals from different receptor systems are integrated. The multitude of stimuli includes cytokines, growth factors and hormones, the binding of which ultimately leads to processes such as the regulation of immune reactions and cell growth, survival and differentiation.

The highly conserved transmission path essentially comprises three processing levels for incoming information, depending on the function of the respective components:

Ligand binding to the receptor triggers conformational changes in receptor molecules.
This steric receptor change brings two Janus kinases (JAK), which are bound to the receptor or to receptor subunits, in close proximity and thus enable transphosphorylation. The activated JAKs then phosphorylate further targets.
The main goals of phosphorylation are STAT (Signal Transducers and Activators of Transcription). These transcription factors are inactive in the cytoplasm until phosphorylation by the JAKs. As soon as a conserved tyrosine is phosphorylated at the C-terminus of the STAT, it can act together with SH2 domains as a dimerization interface of another STAT. These activated STAT dimers are then transferred to the cell nucleus and bind to certain DNA motifs in order to activate the transcription of the target gene.
In addition, these processes are negatively regulated at various levels.

SOCS (Suppressors of Cytokine Signaling) gene transcription is stimulated by activated STATs. SOCS deactivate signal transmission by binding to the phosphorylated JAKs or receptors or by enabling JAK ubiquitination.
Protein inhibitors from activated STATs (PIAS) bind to activated STATs and thus prevent them from binding DNA.
PTPs (protein tyrosine phosphatases) reverse JAK activity.
The prototype of the JAK-STAT signal path is rather linear. Nevertheless, there is also considerable mutual interference from others and through other signal cascades such as MAPK signaling pathways and JAK-independent STAT phosphorylation by RTKs (receptor tyrosine kinases).

DNA repair

DNA is the carrier of the genetic information that defines every living being. The genetic code defined in the DNA is an essential part of processes from the subcellular level to the appearance and function of the organism as a whole. Nevertheless, DNA is at risk from endogenous sources such as hydrolysis, oxidation, alkylation or replication errors. In addition, there is ionizing radiation, UV radiation and a number of chemical reagents that form external risk factors for the integrity of the DNA.

Unlike RNA and proteins, DNA is not broken down and synthesized as a result of damage. Instead, there are numerous repair signaling pathways that ensure that the DNA remains intact. Francis Crick noted in 1974 that “we completely ignored the possible role of enzymes in [DNA] repair. It was only later that I discovered that the DNA is so valuable that several separate mechanisms could be involved. ”

This premonition has been confirmed: Since then, more than 100 genes have been identified that are involved in the complex network of DNA repair signaling pathways. Depending on the type of lesion, DNA damage can be repaired using six different signaling pathways: chemical modification, nucleotide incorrect installation and cross-linking are remedied by direct repair (DR), mismatch repair (MMR) or nucleotide excision repair. Single-strand breaks in DNA are repaired by base excision, and highly mutagenic double-strand breaks are finally repaired by a series of complex signaling pathways based on homologous recombination (HR) with the sister chromatid (in the S or G2 phase of the cell cycle) or the non-homologous end linkage (non-homologous end-joining, NHEJ). In the event that a DNA lesion cannot be repaired in time, special DNA polymerases enable translational synthesis (TLS), which prevents the delay in the DNA replication fork. Mutations that disable parts of these repair signaling pathways can trigger diseases such as Xeroderma pigmentosum, Louis Bar syndrome, Fanconi anemia and a predisposition to cancer.

Furthermore, these repair mechanisms are of great interest for the approach of targeted genome editing, which makes use of the cellular DNA repair mechanisms.

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