Repair mechanisms of the organism and their genetic control

Reparation mechanisms prevent species from being threatened by selection and mutation. They were described mainly in bacteria, there are still many unknowns in eukaryotes.

Photoreactivation

Irradiation with UV-light creates thymine dimers in DNA. The enzyme DNA photolyase binds to these dimers. Its fission activity is dependent on the energy of visible light, especially the blue fraction. It cleaves dimers after irradiation. In the dark, the enzyme binds to the DNA but does not cleave the dimers. DNA photolyase is able to cleave other dimers as well.

• Significantly applied to bacteria;
• in multicellular organisms, this process is only applied in the surface layer of cells.

Excessive Fixes

• Part of the replication process;
• with a high rate of insertion of nucleotides into a new chain, there is a high frequency of misinsertion of bases;
• the first check of correct pairing in the newly synthesized DNA chain and in the matrix is provided by a polypeptide that is part of the DNA polymerase III complex;
• require the participation of at least 17 polypeptides. A mutation of any of them leads to the development of a syndrome with the risk of neoplasia and other symptoms.

Repair takes place in 3 steps

1. DNA endonuclease recognizes misplaced bases, binds to and breaks the DNA chain, cleaves the wrong sequences;
2. DNA polymerase I uses the 3-OH of the repaired chain, fills in the nucleotide sequence gap;
3. DNA ligase joins the newly synthesized stretch to the continuation of the repaired strand.

Mismatch repair

Mismatch repair is an early post-replication control and repair mechanism. The ability to recognize the template and the newly synthesized strand is important to recognize which of the base pairs is misaligned.

• In E. coli distinction made possible by comparing the methylation of the chains (GATC – methylated template);
• in humans, MutS and MutL protein homologues encoded by 'mutator genes, which do not cause mutations, but repair them. They enable cell replication to be delayed until DNA repair is completed or, in case of greater DNA damage, induce cell apoptosis as a final protection against the formation of a clone of cells with mutated DNA.

Mutations of these genes make mismatch impossible and the resulting mutations are transmitted to the next generations. It can lead to the formation of a tumor.

• Mismatch repair genes in humans: hMSH2, hMLH1, hMS1, hPMS2.

Post-Replication Repairs

If DNA polymerase III. at E. coli reaches the thymine dimer in the template, stops working, and detaches from the chain. The synthesis of a new chain is restarted by joining the primase at the place of the closest signal frequency with a dimer, the resulting gap can be filled by recombination by the action of the RecA protein (it mediates the pairing of homologous chains and the filling of the gap from the second double strand). The missing part of the chain will be completed by DNA polymerase I and joined by DNA ligase. If the thymine dimer is not removed by the excision mechanism, the post-replication repair process must be repeated with each replication.

SOS repair

It is the last "desperate" attempt to survive when the bacterium's DNA is seriously damaged. The proteins umuC and umuD enable the replication of damaged and unrepaired sections of the DNA template. This type of repair increases the frequency of replication errors.

Function and biological role of transcription factors

Regulation of basal transcription

• GTFs (general transcription factors) – necessary for transcription
• many of them do not bind to DNA, but are part of a preinitiation complex that reacts directly with RNA polymerase II
• most common: TFIIA, TFIIB, TFIID (includes a subunit called TATA binding protein (TBP) - binds specifically to the TATA box sequence), TFIIE, TFIIF and TFIIH

Cell development

• based on signals, they regulate cell differentiation and determination
• the TF family Hox is important for proper body organization
• TF coded SRY (Sex-determining region of Y) – determination of human sex

Response to Intercellular Signals

• part of the signaling cascade (activation x suppression)
• e.g. estrogenic signaling: TF is part of the estrogen receptor, which after activation travels to the nucleus, where it regulates the transcription of certain genes

Response to the external environment

• TFs also regulate signaling cascades of exogenous origin
• Heat shock factor (HSF) - activates genes enabling survival at higher temperatures
• Hypoxia inducible factor (HIF) - survival in an environment with a lack of oxygen

Cell cycle control

• hl. TFs that are oncogenes (eg myc) and tumor suppressors (eg p53) - role in cell growth and apoptosis

Syndromes caused by malfunctions of repair mechanisms

in humans, a number of "hereditary syndromes" are known, which are associated with increased sensitivity to "mutagenic influences" and may be caused by malfunctions of repair mechanisms.

Xenoderma pigmentosum

• most explored
• 'recessively inherited disease with an incidence of 1:70,000
• sufferers are sensitive to 'UV radiation
• tanning causes irregular pigmentation and at an early age 'skin cancers appear in them
• the risk of neoplasia of other organs is also increased
• in addition to skin sensitivity, XP patients have various neurological disorders - the explanation is the death of long-lived nerve cells (apoptosis)
• the disease is caused by a defect in the NER 'excision system
• sufferers are unable to repair damage caused by 'UV radiation

An example of a defect in the ``BER system are mutations in the MUTYH gene in humans, causing one of the hereditary forms of ``colorectal cancer.

Bloom Syndrome

• caused by a mutation in the BLM gene, which is involved in the post-replication repair process
• sufferers have chromosomal instability', an increased risk of tumors and are immunodeficient

Links

Related Articles

• Mutation
• DNA
• Mutation
• Mutator Genes
• Hereditary tumor syndromes

References

• KAPRAS, J., M. KOHOUTOVÁ a B. OTOVÁ. Chapters from medical biology and genetics I. 1. edition . Praha : Karolinum, 1996. ISBN 80-7184-322-9.

• SOUKUPOVÁ, M. a F. SOUKUP. Chapters from medical biology and genetics II. 1. edition . Praha : Karolinum, 1998. ISBN 80-7184-581-7.

• KAPRAS, J. a M. KOHOUTOVÁ. Chapters from medical biology and genetics III. 1. edition . Praha : Karolinum, 1999. ISBN 80-246-0001-3.

• ŠTEFÁNEK, Jiří. Medicine, diseases, studies at the 1st Faculty of Medicine UK [online]. [cit. 2009]. <https://www.stefajir.cz/>.