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DNA Replication and Cancer Disease

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Human genome contains all the information necessary to maintain and continue the life, and two basic processes are most important for that. One is a transcription of genetic information which leads to synthesis of proteins and another one is a replication and maintenance of the genomic information itself. Both of these processes are very complicated, involving large macromolecular machines and networks of highly coordinated events requiring protein-protein and protein-nucleic acid interactions. The disruptions in these events often lead to cancers and a variety of other diseases and disorders.

Cancer disease is a disease that causes the growth or reproduction of cells in an uncontrolled or abnormal manner as a result of DNA damage in the cells. To transform a normal cell into a cancer cell, the cells that regulate cell growth and differentiation must be changed. Genetic changes can be existing at various levels and various mechanisms. The gain or loss of an entire chromosome can occur through errors in mitosis. Mutations, changes in the nucleotide sequence of genomic DNA are more general. Replication of the data involved within the DNA of living cells will result some errors (mutations). Complex error correction and error prevention are included to the processes and protect the cell from cancer. If a serious error appears, the damaged cell can self-destruct through programmed cell death, called apoptosis. If the error control processes fail, then the mutations will survive and transmitted to daughter cells.

DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. This process happens in all living organisms and is the basis for biological inheritance. The cell possesses the distinctive property of division, which makes replication of DNA essential. DNA replication is a conserved mechanism that restricts DNA replication to once per cell cycle in eukaryotes. Eukaryotic DNA replication of chromosomal DNA is central for the duplication of a cell and is necessary for the maintenance of the eukaryotic genome. DNA replication is the action of DNA polymerases synthesizing a DNA strand complementary to the original template strand.

DNA polymerases are major enzymes that synthesize DNA molecules from deoxyribonucleotides, the building blocks of DNA. These enzymes are essential for DNA replication and usually work in pairs to create two identical DNA strands that match the existing ones. Pol α (alpha), Pol δ (delta), and Pol ε (epsilon) are members of Family B Polymerases, which found in eukaryotes and are at the core enzymes of the coping process. They work together to do duplicate the bulk of the genome.

Pol α complex (pol α-DNA primase complex) consists of four subunits: the catalytic subunit POLA1, the regulatory subunit POLA2, and the small and the large primase subunits PRIM1 and PRIM2 respectively. At first, primase has created the RNA primer, then Pol α starts replication elongating the primer with ~20 nucleotides. Pol δ is expressed by genes POLD1, creating the catalytic subunit, POLD2, POLD3, and POLD4 creating the other subunits that interact with Proliferating Cell Nuclear Antigen (PCNA), which is a DNA clamp that allows Pol δ to possess processivity. Pol ε is encoded by the POLE1, the catalytic subunit, POLE2, and POLE3 gene. It has been reported that the function of Pol ε is to extend the leading strand during replication, while Pol δ primarily replicates the lagging strand; however, recent research suggested that Pol δ could have a role in replicating the leading strand of DNA as well. Pol ε’s C-terminus region is thought to be essential to cell vitality as well.

It is thought that C-terminus region provides a checkpoint before entering anaphase, provide stability to the holoenzyme, and add proteins to the holoenzyme crucial for initiation of replication. Pol ε is encoded by four subunits: POLE (central catalytic unit), POLE2 (subunit 2), POLE3 (subunit 3), and POLE4 (subunit 4). Recent evidence suggests that it plays an essential role in leading strand DNA synthesis and base excision repair. The eukaryotic DNA polymerase δ (Pol δ) takes part in genome replication, homologous recombination, DNA repair and damage tolerance. Regulation of the plethora of Pol δ functions depends on the interaction between the second (p50) and third (p66) non-catalytic subunits.

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