Theme 6: What Causes Cancer?
By the end of this section, you will be able to:
- Explain the process of DNA replication
- Differentiate between mismatch repair and nucelotide excision repair
- Explain the role of ultraviolet light in causing DNA mutations
When a cell divides, it is important that each daughter cell receives an identical copy of the DNA. This is accomplished by the process of DNA replication. The replication of DNA occurs during the synthesis phase, or S phase, of the cell cycle, before the cell enters mitosis or meiosis.
The elucidation of the structure of the double helix provided a hint as to how DNA is copied. Recall that adenine nucleotides pair with thymine nucleotides, and cytosine with guanine. This means that the two strands are complementary to each other. For example, a strand of DNA with a nucleotide sequence of AGTCATGA will have a complementary strand with the sequence TCAGTACT (Figure 1).
Because of the complementarity of the two strands, having one strand means that it is possible to recreate the other strand. This model for replication suggests that the two strands of the double helix separate during replication, and each strand serves as a template from which the new complementary strand is copied (Figure 2).
During DNA replication, each of the two strands that make up the double helix serves as a template from which new strands are copied. The new strand will be complementary to the parental or “old” strand. Each new double strand consists of one parental strand and one new daughter strand. This is known as semiconservative replication. When two DNA copies are formed, they have an identical sequence of nucleotide bases and are divided equally into two daughter cells.
DNA Replication in Eukaryotes
The process of DNA replication can be summarized as follows:
- DNA unwinds at the origin of replication.
- New bases are added to the complementary parental strands. The matching of free nucleotides to the parental strands is accomplished by an enzyme called DNA polymerase.
- Primers are removed, new DNA nucleotides are put in place of the primers and the backbone is sealed by DNA ligase.
DNA polymerase can make mistakes while adding nucleotides. It edits the DNA by proofreading every newly added base. Incorrect bases are removed and replaced by the correct base, and then polymerization continues (Figure 3a). Most mistakes are corrected during replication, although when this does not happen, the mismatch repair mechanism is employed. Mismatch repair enzymes recognize the wrongly incorporated base and excise it from the DNA, replacing it with the correct base (Figure 3b). In yet another type of repair, nucleotide excision repair, the DNA double strand is unwound and separated, the incorrect bases are removed along with a few bases on the 5′ and 3′ end, and these are replaced by copying the template with the help of DNA polymerase (Figure 3c). Nucleotide excision repair is particularly important in correcting thymine dimers, which are primarily caused by ultraviolet light. In a thymine dimer, two thymine nucleotides adjacent to each other on one strand are covalently bonded to each other rather than their complementary bases. If the dimer is not removed and repaired it will lead to a mutation. Individuals with flaws in their nucleotide excision repair genes show extreme sensitivity to sunlight and develop skin cancers early in life.
Most mistakes are corrected; if they are not, they may result in a mutation—defined as a permanent change in the DNA sequence. Mutations in repair genes may lead to serious consequences like cancer.
DNA replicates by a semi-conservative method in which each of the two parental DNA strands act as a template for new DNA to be synthesized. After replication, each DNA has one parental or “old” strand, and one daughter or “new” strand. Errors made during replication are typically repaired. If they are not, mutations can result.
- DNA ligase
- the enzyme that catalyzes the joining of DNA fragments together
- DNA polymerase
- an enzyme that synthesizes a new strand of DNA complementary to a template strand
- an enzyme that helps to open up the DNA helix during DNA replication by breaking the hydrogen bonds
- mismatch repair
- a form of DNA repair in which non-complementary nucleotides are recognized, excised, and replaced with correct nucleotides
- a permanent variation in the nucleotide sequence of a genome
- nucleotide excision repair
- a form of DNA repair in which the DNA molecule is unwound and separated in the region of the nucleotide damage, the damaged nucleotides are removed and replaced with new nucleotides using the complementary strand, and the DNA strand is resealed and allowed to rejoin its complement
- a short stretch of RNA nucleotides that is required to initiate replication and allow DNA polymerase to bind and begin replication
- replication fork
- the Y-shaped structure formed during the initiation of replication
- semiconservative replication
- the method used to replicate DNA in which the double-stranded molecule is separated and each strand acts as a template for a new strand to be synthesized, so the resulting DNA molecules are composed of one new strand of nucleotides and one old strand of nucleotides
- an enzyme that contains a catalytic part and an inbuilt RNA template; it functions to maintain telomeres at chromosome ends
- the DNA at the end of linear chromosomes