Pathway choice in DNA double strand break repair: observations of a balancing act

Genomic integrity and faithful replication are essential to prevent mutations and chromosomal rearrangements, which may otherwise lead to diseases and in some cases even death. DNA damage is generated by several different genotoxic agents such as reactive oxygen species, UV light from the sun and mutagenic chemicals [1]. These agents cause many types of DNA damage, ranging from base damage to double strand breaks (DSBs). To protect the genome from the deleterious effects of these lesions, several mechanisms have evolved that detect and repair DNA damage. Together with mechanisms that regulate cell cycle progression and cell death pathways this is known as the DNA damage response (DDR).In this review we concentrate on DSBs, which are among the most cytotoxic types of DNA damage. The therapeutic effect of several commonly used cancer treatment modalities, such as ionizing radiation and the chemotherapeutic doxorubicin, are based on the cell-killing effect of DSBs. However, DSBs are also the initiating lesion of disease-causing chromosomal translocations in cancer. Therefore, it is important to understand the intricate regulation of the DDR upon DSB formation. We mainly concentrate on the two main DSB repair pathways, Non-homologous end joining (NHEJ) and Homologous recombination (HR), with a special emphasis on the balance between both repair mechanisms in health and disease.NHEJ is a relatively simple DSB repair pathway (Figure 1). Both ends of the break are first bound by the Ku70/Ku80 heterodimer, which then recruits the catalytic subunit of the DNA dependent protein kinase (DNA-PKcs) [2]. If necessary, the ends can be trimmed by nucleases (such as Artemis) or filled in by DNA polymerases (such as Polμ or Polλ) to create compatible ends [3]. Finally, the ligation complex, consisting of DNA ligase IV, X-ray cross-complementation group 4 (XRCC4) and Xrcc4 like factor (XLF)/Cernunnos ligates the ends [4,5]. NHEJ can take place throughout the cell cycle. For an extensi