as cisplatinum, which was newly synthesized in the twentieth century, an indication that novelty or uniqueness is no barrier to the repair of DNA damage.
Repair of DSBs involves a number of biochemically distinct processes. Direct rejoining of the broken ends occurs by several mechanisms, generally described as NHEJ. A fast NHEJ process involves end-binding proteins (Ku70, Ku80, and DNA-PK; Baumann and West 1998; Critchlow and Jackson 1998; Zhao and others 2000), and a slower process involves the hMre11/hRad50/Nbs1 DNA-binding and exonuclease complex that appears to act on refractory, complex breaks (Haber 1998; Petrini 1999). A more complicated rejoining process—homologous recombination—depends on matching damaged DNA with its identical sequence in a sister chromatid after DNA replication or in the homologous chromosome in diploid cells. This process depends on the hRad51 protein, which facilitates homologous pairing, and accessory proteins, such as hRad52, hRad54, XRCC2, and XRCC3 (Thompson 1996). How cells coordinate these processes and determine which should be used under various circumstances is unknown. Coordination may be under the control of the Brca1 and Brca2 proteins. Brca1 binds to unusual DNA structures (Parvin 2001) and is found in a large complex that contains many repair and replication proteins (Wang and others 2000).
The proteins directly involved in DNA strand-break repair do not appear to be inducible (Tusher and others 2001) or to be strongly influenced by p53 functions, except where recombination is involved. Radiation-induced genes represent predominantly cellular signaling molecules, particularly those induced by transactivation by p53. Radiation does, however, activate a series of protein kinases, of which ATM (ataxia-telangiectasia-mutated) is the most prominent, that modify the activity of many other proteins in the repair pathways (Bakkenist and Kastan 2003).
DSBs begin to rejoin rapidly after irradiation, with half-times of about 10 min or less (Ward and others 1991). This rapid rejoining involves accumulation of the end-binding proteins Ku70 and Ku80, DNA-PK kinase, the DNA ligase IV-XRCC4 heterodimer, PARP, and others (Figure 1-10). The same factors are also an integral part of the normal process of immunologic rearrangement (Labhart 1999). Conceivably, if the LMDS contains damaged bases, the ends will also require repair steps involving glycosylases, apurinic endonuclease, and DNA polymerase β. Attempted repair by these BER enzymes can enhance DSB formation and loss of base pairs, which then must be repaired by NHEJ (Blaisdell and Wallace 2001). Attempted BER of LMDS in human lymphoblastoid cells produces lethal and mutagenic DSBs (Yang and others, 2004). Small deletions associated with NHEJ have been mapped by sequencing techniques and range up to about 10 nucleotides (Daza and others 1996).