Figure 5–46 Nonhomologous end joining. (A) A central role is played by the Ku protein, a heterodimer that grasps the broken chromosome ends. The additional proteins shown are needed to hold the broken ends together while they are processed and eventually joined covalently. (B) Three-dimensional structure of a Ku heterodimer bound to the end of a duplex DNA fragment. The Ku protein is also essential for V(D)J joining, a specific recombination process through which antibody and T cell receptor diversity is generated in developing B and T cells (discussed in Chapter 24). V(D)J joining and nonhomologous end joining show many similarities in mechanism but the former relies on specific double-strand breaks produced deliberately by the cell.  (B, from J.R. Walker, R.A. Corpina, and  J. Goldberg, Nature 412:607–614, 2001. With permission from Macmillan  Publishers Ltd.)
DNA Damage Delays Progression of the Cell Cycle
We have just seen that cells contain multiple enzyme systems that can recognize and repair many types of DNA damage (Movie 5.7). Because of the importance of maintaining intact, undamaged DNA from generation to generation, eukaryotic cells have an additional mechanism that maximizes the effectiveness of their DNA repair enzymes: they delay progression of the cell cycle until DNA repair is complete. As discussed in detail in Chapter 17, the orderly progression of the cell cycle is stopped if damaged DNA is detected, and it restarts when the damage has been repaired. Thus, in mammalian cells, the presence of DNA damage can block entry from G1 into S phase, it can slow S phase once it has begun, and it can block the transition from G2 phase to M phase. These delays facilitate DNA repair by providing the time needed for the repair to reach completion.
DNA damage also results in an increased synthesis of some DNA repair enzymes. This response depends on special signaling proteins that sense DNA damage and up-regulate the appropriate DNA repair enzymes. The importance of this mechanism is revealed by the phenotype of humans who are born with defects in the gene that encodes the ATM protein. These individuals have the disease ataxia telangiectasia (AT ), the symptoms of which include neurodegeneration, a predisposition to cancer, and genome instability. The ATM protein is a large kinase needed to generate the intracellular signals that sound the alarm in response to many types of spontaneous DNA damage (see Figure 17–62), and individuals with defects in this protein therefore suffer from the effects of unrepaired DNA lesions.
Genetic information can be stored stably in DNA sequences only because a large set of DNA repair enzymes continuously scan the DNA and replace any damaged nucleotides. Most types of DNA repair depend on the presence of a separate copy of the genetic information in each of the two strands of the DNA double helix. An accidental lesion on one strand can therefore be cut out by a repair enzyme and a corrected strand resynthesized by reference to the information in the undamaged strand.
Most of the damage to DNA bases is excised by one of two major DNA repair pathways. In base excision repair, the altered base is removed by a DNA glycosylase enzyme, followed by excision of the resulting sugar phosphate. In nucleotide excision repair, a small section of the DNA strand surrounding the damage is removed from the DNA double helix as an oligonucleotide. In both cases, the gap left in the DNA helix is filled in by the sequential action of DNA polymerase and DNA ligase, using the undamaged DNA strand as the template. Some types of DNA damage can be repaired by a different strategy—the direct chemical reversal of the damage— which is carried out by specialized repair proteins. When DNA damage is excessive, a special class of inaccurate DNA polymerases, called translesion polymerases, is used to bypass the damage, allowing the cell to survive but sometimes creating permanent mutations at the sites of damage.