Allelic polymorphisms of dna repair genes and their influence on the formation of resistance to the development of bronchopulmonary pathology under the action of industrial aerosols

Abstract

In Ukraine, annually, 6-8 thousand occupational diseases are registered, 70% of those are bronchopulmonary pathologies (BPP) [1]. The nature, clinical course and complications of BPP depend on the composition of the industrial aerosols, their aggressiveness and genetic predispositions and immunological characteristics of the individual [2]. In living organisms, there are various systems that protect from exogenous damaging agents, such as DNA repair [3-7]. There are 4 basic DNA repair systems: base-excision repair (BER); nucleotide excision repair (NER); double-strand break repair (DSBR), which is divided into homologous recombination (HR) and non-homologous end joining (NHEJ); mismatch repair (MMR). Most of the damages to DNA (up to 70%) are removed by BER [8]. The genes encoding for BER are characterized by a high level of polymorphism, which, due to changes in the activity of reparative enzymes, can affect individual sensitivity to the actions of various genotoxic agents, including tobacco smoke and industrial aerosols. The XRCC1 gene (X-ray-repair cross-complementing group 1) is localized on the 19-th chromosome (19q13.2). A protein that it encodes, regulates the regeneration of DNA molecules that have been damaged by ionizing radiation and alkylating agents [3, 8-9]. The XRCC3 gene (X-ray-repair cross-complementing group 3) is involved in recombinant DNA repair and double-stranded DNA breaks [10]. The protein products of the NER genesare involved in the removal of the damaged nucleotides with the subsequent restoration of the structure of the DNA molecule, through the recognition and correction of basal cross-linking [11]. The XPD protein (xeroderma pigmentosum group D) functions at the beginning of the synthesis of all proteins as a subunit of the complex protein TFIIH, a complementary factor of RNA polymerase II [5, 6]. The main function of the ERCC1 gene (Excision repair cross complementing 1) is nucleotide recovery [11]. Variants of DSBR errors lead to different types of mutations and chromosome rearrangements that induce a genome instability and carcinogenesis [3, 6]. The gene XRCC7 (X-ray-repair cross-complementing group 7) is located on the 8th chromosome (8q11), encodes a protein which is a large catalytic subunit of the DNA-PC complex (DNA-PKc), which forms an active protein kinase with Ku and initiates recovery by NHEJ [8, 13, 14]. The ataxia-telangiectasia mutation (ATM) gene is localized on the 11th chromosome (11q22-23), encoding the DNA-dependent proteincanase, localized mainly in the nucleus. The carriers of mutant alleles are characterized by sensitivity to radiation, multiple defects in development, predisposition to oncology [15]. A special place among the DNA repair systems belongs to the MMR, thanks to which it is possible to preserve genetic information even when there is a high number of mutations. The MLH1 gene (mutL (E. coli) homolog 1) is located on chromosome 3, encoding a protein that regulates the replacement of improperly coupled DNA bases and is inactivated by methylation [16]. Consequently, there is a lot of data on DNA repair of SNPs associated with high risk factors for lung carcinogenesis due to tobacco smoke, therefore we decided to study these molecular markers in people working in an environment in which industrial aerosols have an impact on them.