How Can Damaged DNA be Repaired

Cellular DNA is subjected to damages by both exogenous and endogenous processes. Generally, human genome may undergo millions of damages per day. The changes in the genome cause errors in gene expression, producing proteins with altered structures. Proteins play a major role inside the cell by involving in cellular functions and cell signaling. Therefore, DNA damages may cause non-functional proteins that ultimately lead to cancers. In addition, the changes in the genome may pass to the next cell generation, becoming permanent changes known as mutations. Therefore, it is critical to repair DNA damages, and a number of cellular mechanisms are involved in this process. Some of these repair mechanisms include base excision repair, nucleotide excision repair, and double-strand break repair.

Key Areas Covered

1. What are DNA Damages
     – Definition, Causes, Types
2. How Can Damaged DNA be Repaired
     – Damage Repair Mechanisms
3. What Happens If DNA Damages are Not Repaired
     – Cellular Responses for Damaged Cellular DNA

Key Terms: Direct Reversal of Bases, DNA Damage, Double-Strand Damage Repair, Endogenous Factors, Exogenous Factors, Single-Strand Damage Repair

What are DNA Damages

DNA damages are the alterations of the chemical structure of the DNA, including missing base from the DNA backbone, chemically-changed bases or double-strand breaks. Both environmental reasons (exogenous factors) and cellular sources such as internal metabolic processes (endogenous factors) cause damage to DNA. Broken DNA is shown in figure 1.

Figure 1: Broken DNA

Causes: Exogenous Factors

Exogenous factors can be either physical or chemical mutagens. The physical mutagens are mainly UV radiation that generates free radicals. Free radicals cause both single-strand and double-strand breaks. Chemical mutagens such as alkyl groups and nitrogen mustard compounds bind covalently to DNA bases. 

Causes: Endogenous Factors

Biochemical reactions of the cell may also partially or completely digest the bases in DNA. Some of the biochemical reactions that change the chemical structure of DNA are described below.

• Depurination – Depurination is the spontaneous breakdown of purine bases from the DNA strand.
• Depyrimidination – Depyrimidination is the spontaneous breakdown of pyrimidine bases from the DNA strand. 
• Deamination – Deamination refers to the loss of amine groups from adenine, guanine, and cytosine bases.
• DNA methylation – DNA methylation is the addition of an alkyl group to the cytosine base in the CpG sites. (Cytosine is followed by guanine).

How Can Damaged DNA be Repaired

Various types of cellular mechanisms are involved in the repair of DNA damages. DNA damage repair mechanisms occur in three levels; direct reversal, single-strand damage repair, and double-strand damage repair.

Direct Reversal

During direct reversal of DNA damages, most of the changes in the base pairs are chemically reversed. Some direct reversal mechanisms are described below.

1. Photoreactivation – UV causes the formation of pyrimidine dimers between adjacent pyrimidine bases. Photoreactivation is the direct reversal of pyrimidine dimers by the action of photolyase. Pyrimidine dimers are shown in figure 2.

Figure 2: Pyrimidine Dimers

2. MGMT – The alkyl groups are removed from bases by methylguanine methyltransferase (MGMT).

Single-Strand Damage Repair

Single-strand damage repair is involved in the repair of damages in one of the DNA strand in the DNA double-strand. Base-excision repair and nucleotide excision repair are the two mechanisms involved in single-strand damage repair.

1. Base-excision repair (BER) – In base-excision repair, single nucleotide changes are cleaved off from the DNA strand by glycosylase and DNA polymerase resynthesizes the correct base. Base excision repair is shown in figure 3.

Figure 3: BER

2. Nucleotide excision repair (NER) – The nucleotide excision repair is involved in the repair of distortions in DNA such as pyrimidine dimers. 12-24 bases are removed from the damages site by endonucleases and DNA polymerase resynthesizes the correct nucleotides.

Double-Strand Damage Repair

Double-strand damage may lead to rearrangement of the chromosomes. Non-homologous end joining (NHEJ) and homologous recombination are the two types of mechanisms involved in the double-strand damage repair. Double-strand damage repair mechanisms are shown in figure 4.

Figure 4: NHEJ and HR

1. Non-homologous end joining (NHEJ) – DNA ligase IV and a cofactor known as XRCC4 hold the two ends of the broken strand and rejoin the ends. The NHEJ relies on the small homologous sequences to detect compatible ends during rejoining.
2. Homologous recombination (HR) – Homologous recombination uses identical or nearly identical regions as a template for repair. Therefore, the sequences in homologous chromosomes are used during this repair.

What Happens If DNA Damages are Not Repaired

If the cells lose their ability to repair DNA damage, three types of cellular responses may occur in the cells with damaged cellular DNA.

1. Senescence or biological aging – the gradual deterioration of functions of cells
2. Apoptosis – DNA damages may trigger cellular cascades of apoptosis
3. Malignancy – development of immortal characteristics such as uncontrolled cell proliferation that leads to cancer.

Conclusion

Both exogenous and endogenous factors cause DNA damages that are readily repaired by cellular mechanisms. Three types of cellular mechanisms are involved in the DNA damage repair. They are the direct reversal of bases, single-strand damage repair, and double-strand damage repair.

Image Courtesy:

1. “Brokechromo” (CC BY-SA 3.0) via Commons Wikimedia
2. “DNA With cyclobutane pyrimidine dimer” By J3D3 – Own work (CC BY-SA 4.0) via Commons Wikimedia
3. “Dna repair base excersion en” By LadyofHats – (Public Domain) via Commons Wikimedia
4. “1756-8935-5-4-3-l” By Hannes Lans, Jurgen A Marteijn and Wim Vermeulen – BioMed Central (CC BY 2.0) via Commons Wikimedia