How Can Errors During DNA Replication Lead to Cancer

Every time the cells of the body divide, its DNA also replicates. During DNA replication, DNA polymerase has to copy around 3 billion base pairs in the human genome. Unfortunately, DNA polymerase may insert wrong nucleotides to the newly-synthesized DNA as well. Several cellular mechanisms are employed to repair these incorrect bases in the sequence; some of these mechanisms include proofreading, strand-directed mismatch repair, excision repair, direct reversal of DNA damage, and double-strand break repair. However, some replication errors may pass to the next cell generation through cell division, becoming mutations. These mutations, known as somatic mutations, may accumulate in the body as cells divide, resulting in cancers. Some cancer mutations such as germ-line mutations may be inherited to the next generation as well.

Key Areas Covered

1. How Do the Errors Occur During DNA Replication
     – Complementary Base Pairing,
2. How are the Errors in DNA Replication Fixed
     – DNA Repair Mechanisms
3. How Can Errors During DNA Replication Lead to Cancer
     – Mutations in the Cancer-Causing Genes

Key Terms: Cancer, Cancer-causing Genes, Cell Division, DNA Polymerase, DNA Replication, Mutations, Repair Mechanisms

How Do the Errors Occur During DNA Replication

During DNA replication, DNA polymerase adds complementary nucleotides to the newly-synthesizing DNA strand based on the nucleotides in the old DNA strand. The common base pairing pattern is the adenine base pairs with guanine and cytosine base pairs with thymine. The complementary base pairing is shown in figure 1.

Figure 1: Complementary Base Pairing

Cause for Errors in DNA Replication

The causes for errors in DNA replication are discussed below.

1. Most replication errors occur due to the mispairing of non-tautomeric nucleotides such as the base pairing of adenine with cytosine and thymine with guanine. The slight shifts in the position of the nucleotides in space are tolerated by the DNA double helix. This type of base mispairing is known as a wobble.
2. Some replication errors occur due to the tautomeric shift of incoming nucleotides. Both purines, as well as pyrimidines, may exist in different chemical forms known as tautomers. Protons occupy different positions within the same structure in different tautomers. Hence, the more common keto form of the nucleotide bases is shifted into the rarer enol form. The tautomerization of guanine is shown in figure 2.

Figure 1: Guanine Tautomerization

3. Insertions or deletions of nucleotides can occur during strand slippage in DNA replication. They may also produce errors in DNA replication.

How are the Errors in DNA Replication Fixed

The errors in DNA replication can be fixed in various ways. Some of them are listed below.

1. Proofreading – DNA polymerase is equipped with mechanisms such as ‘double-check’ the incoming nucleotide and 3′ to 5′ exonuclease activity in order to correct the mispairing bases.
2. Strand-directed mismatch repair – The Mut protein complex recognizes the distortions in the DNA strand caused by mispaired bases and corrects them.
3. Nucleotide Excision repair (NER) – The NER is a mechanism for correcting UV damages to the DNA strand.
4. Direct reversal of DNA damage – The direct reversal of DNA damage is involved in the removal of the DNA damage followed by the resynthesis of the DNA strand.
5. Double-strand break repair – Nonhomologous end-joining and homologous recombination are two types of mechanisms involved in the double-strand break repair.

How Can Errors During DNA Replication Lead to Cancer

Although most of the mismatched bases are repaired by the above-mentioned mechanisms; however, some of the nucleotide mismatches can pass to the next cell generation through cell division. Then they become mutations by permanently-incorporating into the nucleotide sequence of the genome. However, mutation rates are as low as one mutation per 100 million to 1 billion base pairs in the bacterial genomes and one mistake per 100 to 1,000 nucleotides in the human genome.

Mutations are accumulated within the cell population as they divide. Although mutations produce genetic variations within a population as a positive effect of mutations, most of the mutations cause cancers. Cancer is an abnormal cell growth that is capable of spreading to the other parts of the body. If the abnormal cell growth is not spread to the other parts of the body, it is referred to a tumor. Generally, two third of the mutations cause cancers. The mutations in the genes that are responsible for the control of the cell division and cell growth may result in cancers. Some cancer-causing genes are tumor suppressor genes, DNA repair genes, and proto-oncogenes. Some of the mutations that cause cancers are shown in figure 3.

Figure 3: Mutations that Cause Cancers

Cancer-Causing Genes

Tumor Suppressor Genes

The tumor suppressor genes are a type of protective genes as they limit the cell growth by monitoring the rate of the cell division and cell death. The mutation of a tumor suppressor gene causes uncontrolled cell growth, forming a cell mass known as a tumor. Some of the tumor suppressor genes are p53, BRCA1, and BRCA2. 

Proto-oncogenes

The mutated proto-oncogenes are known as oncogenes. Oncogenes have a potential to cause cancer. The mutations of oncogenes are not inherited. Two common oncogenes are HER2 and ras. The HER2 gene is involved in controlling the cancer growth and spread. The ras gene family is encoded for the proteins in the cell growth, cell death, and cell communication pathways.

DNA-repair Genes

DNA repair genes are encoded for the proteins that are involved in the fixation of the errors in DNA replication. The mutations in these genes produce defective proteins that are unable to repair the errors that cause cancers. As an example, DNA ligase is an enzyme involved in the ligation of nicked DNA. The mutations in DNA ligase gene allow the accumulation of nicked DNA in the genome, leading to cancers. DNA ligase, which is encircled in the DNA double helix is shown in figure 4.

Figure 4: DNA Ligase

In humans, if a considerable amount of somatic mutations (mutations in body cells) are accumulated in a particular tissue over the course of the lifetime, it may cause cancer. Somatic mutations are also known as acquired mutations. The first somatic mutation recognized as causing cancer is mutated HRAS gene, a proto-oncogene. It causes cancer in the bladder. About 50% of the cancers are caused by somatic mutations of p53 gene. Some of the germ-line mutations (mutations in germ cells) such as colorectal cancers pass into the offspring. Germ-line mutations in BRCA1 and BRCA2 gene cause hereditary ovarian or breast cancers.

Conclusion

Errors can be incorporated into the DNA strand during DNA replication. Several mechanisms are involved in the repair of errors caused by DNA replication. However, some of the errors pass to the next cell generation, causing mutations. The mutations in cancer-causing genes lead to the induction of cancer formation.

Reference:

1. Pray, Leslie A. “DNA Replication and Causes of Mutation.” Nature News, Nature Publishing Group, Available here.
2.“The Genetics of Cancer.” Cancer.Net, 28 Aug. 2015, Available here.

Image Courtesy:

1. “0322 DNA Nucleotides” By OpenStax – (CC BY 4.0) via Commons Wikimedia
2. “Guanine” By Mrbean427 – guanine tautaumerization (CC BY-SA 3.0) via Commons Wikimedia
3. “Cancer requires multiple mutations from NIHen” (Public Domain) via Commons Wikimedia
4. “DNA Repair” By Tom Ellenberger, Washington University School of Medicine in St. Louis. – Biomedical Beat, Cool Image Gallery (Public Domain) via Commons Wikimedia