Polymorphisms of DNA Repair Genes in Thyroid Cancer

Abstract

The incidence of thyroid cancer, one of the most common forms of endocrine cancer, is increasing rapidly worldwide in developed and developing countries. Various risk factors can increase susceptibility to thyroid cancer, but particular emphasis is put on the role of DNA repair genes, which have a significant impact on genome stability. Polymorphisms of these genes can increase the risk of developing thyroid cancer by affecting their function. In this article, we present a concise review on the most common polymorphisms of selected DNA repair genes that may influence the risk of thyroid cancer. We point out significant differences in the frequency of these polymorphisms between various populations and their potential relationship with susceptibility to the disease. A more complete understanding of these differences may lead to the development of effective prevention strategies and targeted therapies for thyroid cancer. Simultaneously, there is a need for further research on the role of polymorphisms of previously uninvestigated DNA repair genes in the context of thyroid cancer, which may contribute to filling the knowledge gaps on this subject.

Keywords: DNA damage response; DNA repair genes; follicular thyroid cancer; papillary thyroid cancer; polymorphism.

Figure 1

Summary of DNA repair mechanisms described in this manuscript. The base excision repair (BER) pathway involves the repair of damaged bases that are cleaved by DNA glycosylases, i.e., 8-oxoguanine-DNA glycosylase 1 (OGG1) and adenine DNA glycosylase (MUTYH), leading to the formation of apurinic/apyrimidinic sites (AP sites), which constitute substrate for DNA nuclease (APE1). Then, polymerase beta (POLβ) synthesizes the missing nucleotide, and ligase III (LIGIII) in a complex with XRCC1 restores the missing phosphodiester bond. AP sites are easily converted to single-strand breaks (SSBs), which are detected by poly(ADP-ribose) polymerase-1 (PARP-1). The damage site is marked by Ser139-phosphorylated H2AX (γH2AX), replication protein A (RPA), and the mediator of DNA damage checkpoint protein 1 (MDC-1), resulting in the recruitment of ATR kinase and phosphorylation of checkpoint kinase 1 (CHK1). Unrepaired SSBs can be converted to double-strand breaks (DSBs), which are detected by the MRN complex, composed of meiotic recombination 11/radiation sensitive 50/nibrin proteins (MRE11/RAD50/NBS1). The signal requires further amplification and transduction using the ataxia telangiectasia mutated (ATM) transducer protein kinase, which, as a result of interaction with the C-terminus of NBS1, becomes autophosphorylated and localizes to the site of damage. Checkpoint kinase 2 (CHK2) constitutes one of the targets of ATM kinase. Phosphorylated CHK1 and CHK2 kinases interact with the cellular tumor antigen p53 (TP53), which acts as a transcription regulator and determines the choice between DNA repair, cell cycle arrest, and apoptosis. TP53 can interact with APE1 and POLβ in the BER pathway. Repair of DSBs can be carried out by non-homologous end joining (NHEJ) or homologous recombination (HR). In the case of NHEJ, DNA-dependent protein kinase catalytic subunits (DNA-PKcs) and KU proteins are expressed, which combine with non-homologous end-joining factor 1 (XLF) and ligase 4 (LIG4) to form a repair complex. Meanwhile, in HR repair, the MRN complex recruits CtBP-interacting protein (CtIP), which binds to the MRN complex and causes activation of the endonucleolytic properties of Mre11. Mre11 works as an exonuclease that triggers degradation of the fragment, which results in the formation of a short single-stranded DNA fragment, and exonuclease 1 (EXO1) further degrades the fragment in the 3′-->5′ direction. On the side of the DNA break, the single-stranded fragment is covered with RPA proteins. Breast cancer type 2 susceptibility protein 2 (BRCA2) is recruited, which co-localizes with the DNA repair protein RAD51 homolog 1 (RAD51) and promotes homology search and strand invasion, resulting in DNA damage repair. Created with BioRender.com (accessed on 28 February 2024).