MEDICAL BIOLOGY, ANATOMY, HUMAN PHYSIOLOGY AND PATHOLOGY - Ya.I. Fedoniuk 2010

BIOLOGY

CHAPTER 1. BIOLOGICAL FOUNDATIONS OF HUMAN VITAL ACTIVITY

1.3. MOLECULAR-GENETIC AND CELLULAR LEVELS OF LIFE ORGANIZATION

1.3.3. Hereditary Apparatus of Eukaryotic Cells and its Functioning - Molecular Level

DNA Repair

Over the course of evolution, Cells have developed specific mechanisms that ensure the stability of hereditary material (DNA) and protect it against Mutations. Without these mechanisms, organisms would perish from the effects of natural mutagens due to the exceptionally high frequency of genetic DNA damage. Most DNA Lesions, which serve as potential sources of mutations, are eliminated through several repair mechanisms. Repair (Latin *reparatio* – restoration) is The process of restoring the Introduction/19.html">Primary Structure of DNA following Damage caused by mutagens. Both light and dark Cell/23.html">DNA Repair Mechanisms are recognized. All of them are enzymatic in nature, correct only single-stranded DNA lesions, and are controlled by specialized genes.

Light repair (photoreactivation) utilizes visible light energy to eliminate damage caused exclusively by ultraviolet (UV) rays. Such damage typically manifests as dimers—linked adjacent pyrimidine bases (predominantly T-T) within the same DNA strand. The Mechanism of light repair is as follows: an enzyme belonging to the photolyase family specifically binds to the UV-irradiated region of DNA, is activated by daylight quanta, and subsequently dissociates; as it detaches, the enzyme simultaneously splits the dimers, thereby restoring the normal DNA Structure. Light within the blue region of the spectrum is the most effective for photoreactivation.

Dark (excision) repair, unlike photoreactivation: 1) does not require visible light energy; 2) eliminates damage caused not only by ultraviolet rays but also by other Mutagenic Factors; 3) proceeds via the excision of the damaged DNA fragment (*excisio* – to cut out).

The stages of dark repair include: 1) recognition of the damaged DNA site by endonuclease; 2) incision of the DNA strand near the lesion by endonuclease; 3) excision of the damaged DNA segment along with the enlargement of the gap on both sides by exonuclease; 4) template-directed synthesis of a DNA fragment ("patch") at the site of the gap (repair Replication); 5) ligation of the newly synthesized segment to the main DNA strand by the enzyme ligase (Fig. 1.42).

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Fig. 1.42. Scheme of DNA Excision Repair

1 – UV light-induced damage to the DNA molecule; 2 – incision of a single DNA strand by endonucleases; 3 – excision of the damaged region by exonucleases; 4 – synthesis of a new strand via polymerase action; 5 – ligation of the newly formed segment by ligases

Both light and dark repair mechanisms eliminate DNA damage prior to replication (prereplicative repair). If these mechanisms fail, the damage is resolved after replication within the daughter DNA strands (postreplicative repair).

Dysfunction of specific repair pathways leads to hereditary disorders, such as xeroderma pigmentosum, Bloom syndrome, Fanconi anemia, and Werner syndrome (premature Aging).

Xeroderma pigmentosum is a hereditary disorder associated with impaired dark DNA repair. It clinically manifests in newborns as photophobia.

A characteristic feature is the heightened sensitivity of the patients' Skin to ultraviolet radiation. This leads to atrophy of exposed skin areas, hyperpigmentation, and potentially skin Cancer. Several forms of xeroderma pigmentosum are distinguished. The inheritance pattern is autosomal dominant and autosomal recessive (Fig. 1.43).

Fig. 1.43. Xeroderma pigmentosum.