Nonhomologous DNA End Joining (NHEJ) and Chromosomal Translocations in Humans

Abstract

Estimates are that double-strand breaks (DSBs) arise in dividing cells about ten times per cell per day. Causes include replication across a nick, free radicals of oxidative metabolism, ionizing radiation, and inadvertent action by enzymes of DNA metabolism (such as failures of type II topoisomerases or cleavage by recombinases at pseudo sequences that look sufficiently similar to the physiologic ones). There are two major double-strand break repair pathways. Homologous recombination (HR) can repair double-strand breaks, but only during S phase and only if there is sufficient homology, usually more than 100 bp. The more general and commonly used pathway is nonhomologous DNA end joining, abbreviated NHEJ. NHEJ can repair a DSB at any time during the cell cycle and does not require any homology, though a few nucleotides of terminal microhomology are often utilized by the NHEJ enzymes, if present. The enzymes of NHEJ include Ku, DNA-PKcs, Artemis, polymerase mu, polymerse lambda, XLF (also called Cernunnos), XRCC4, and DNA ligase IV. These enzymes constitute what some call the classical NHEJ pathway, and in wild type cells, the vast majority of joining events appear to proceed using these components. In rare mammalian cell mutants of ligase IV, for example, much less efficient joining occurs using one of the remaining two ligases, ligase I or III, in a manner that is much more reliant on longer terminal microhomology lengths, such as 7 to 15 nt; this is usually called alternative NHEJ, back-up NHEJ, or microhomology-mediated end joining (MMEJ). NHEJ is present in many prokaryotes, as well as all as eukaryotes, and very similar mechanistic flexibility evolved both convergently and divergently. When two double-strand breaks occur on different chromosomes, then the rejoining is almost always done by NHEJ. The causes of the DSBs in lymphomas most often involve the RAG or AID enzymes that function in the specialized processes of antigen receptor gene rearrangement.

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Repair of Accidental DNA Double-Strand Breaks in the Human Genome and Its Relevance to Vector DNA Integration

“…DNA double-strand breaks (DSBs) are the most severe type of DNA lesions that can be caused by various exogenous and endogenous mechanisms, such as ionizing radiation, reactive oxygen species, topoisomerase poisons, or replication errors [1]. DSBs, if left unrepaired or mis-repaired, lead to cell death or chromosomal aberrations [2,3].…”