## DNA damage is a serious condition that the cell must repair

The cell's response to damage depends on its nature and extent. If the DNA damage is so severe that the cell cannot repair it, programmed cell death (apoptosis) occurs (Figure 5.6). However, if the damage is repairable, the cell cycle is halted, giving the cell time to repair itself. At the same time, repair mechanisms are activated and genes whose products are involved in repairing the damaged DNA are transcribed. After successful repair of the damage and restoration of DNA integrity, the cell cycle can be resumed.

DNA repair mechanisms play an important role in maintaining the integrity of the cell's genetic material and ensures the genetic stability of species by allowing intact DNA to be passed from parents to offspring. As DNA damage has been occurring since the beginning of life on Earth, cells have developed an elaborate network of systems that can repair the negative effects of DNA damage. The variety of repair mechanisms that have evolved from bacteria to humans demonstrates the importance of keeping the number of mutations low.

There are several ways to repair damaged DNA, and which of the available systems the cell chooses to use depends on the specific type of damage. Among the most accurate and commonly used repair methods are excision repairs (Figure 5.7). In this case, the cell must first recognize that DNA damage has occurred and identify the location of the damage. Then the cell machinery must remove either only the damaged base (in what is known as base excision repair) or a short section around the damaged base (in a process called nucleotide excision repair). In both cases, a short gap in the DNA strand is created which is filled by synthesizing a new DNA strand by the enzyme DNA polymerase, using the undamaged complementary DNA chain as a template. Finally, DNA ligase connects the newly synthesized DNA with the rest of the strand.

Single-strand and double-strand breaks are very serious results of DNA damage. If they are not immediately repaired in the cell, the cell cannot function properly and will die. Single-stranded breaks are relatively easy to repair because the broken segment needs to be found, the missing DNA synthesized by DNA polymerase using the unbroken DNA strand as a template, and the new strand is connected by DNA ligase. In contrast, double-stranded breaks are more difficult for the cell to repair. The cell has two ways to repair this damage - non-homologous end joining (NHEJ) and homologous recombination (HR). NHEJ is a faster, less demanding, but also relatively inaccurate repair method in which the cell removes the remnants of the damaged bases from the broken ends of the DNA and joins them together using DNA ligase (Figure 5.7). While some short segments of genetic information may be lost in this type of repair which can have significant consequences, it is even more dangerous to leave the DNA unrepaired. Homologous recombination is a difficult but highly accurate repair method that requires a sister chromatid or homologous chromosome. In this repair mechanism, the cell first finds the ends of the break and creates a 3' overhang by degrading a piece of the 5' strand from the break itself. Such an end is called recombinogenic and is very important because it can insert into the DNA strand of the homologous chromosome. It then moves along the homologous chromosome looking for a complementary sequence of DNA, whereupon DNA polymerase synthesizes the broken part and brings back the strand to its original location. This repaired strand acts as a template for repairing the complementary DNA strand (Figure 5.7). Whether a cell uses HR or NHEJ to repair a break depends not only on the presence of a homologous chromosome or sister chromatid, but also on the organism itself. Human cells prefer the less accurate NHEJ when repairing this type of damage because it is faster and more efficient than HR.

In some cases, the cell also has mechanisms that allow it to tolerate some damage. These include, for example, what is known as translation synthesis. This is a mechanism that allows the cell to replicate its DNA despite damage that could act as a block to replication and thus allows the cell to complete the cell cycle.

Disorders of DNA repair mechanisms lead to increased accumulation of mutations that can result in the development of severe syndromes, such as Xeroderma pigmentosum (causes extreme sensitivity of the skin to UV radiation). They also manifest in severe disorders leading to tumour formation and premature aging, such as Cockayne syndrome (read more in Chapter 9 - When Cells Go Crazy: how a healthy cell becomes cancerous).