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

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

Efficient repair of chromosomal DNA damage is crucial for cells to maintain genome integrity. 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 . DSBs, if left unrepaired or mis-repaired, lead to cell death or chromosomal aberrations . Human cells have evolved two fundamentally different mechanisms for repairing chromosomal DSBs, homologous recombination (HR) and non-homologous end-joining (NHEJ) . NHEJ not only repairs accidental (non-physiological) DSBs, but is also essential for rejoining physiological DSBs that arise in the process of V(D)J recombination in B and T lymphocytes and class switch recombination in mature B cells . A wide variety of proteins have been identified thus far that contribute to the HR and NHEJ machineries. HR is a highly complicated process of DNA transaction, in which Rad51 protein plays an essential role in DNA strand exchange with the aid of several other proteins such as Rad54, Brca2, Rad52, and Rad51 paralogs . For HR to occur, DSBs should be processed (i.e., end-resected) to produce a long 3'-overhang single-stranded DNA , and recent studies have identified a number of proteins involved in end resection or its regulation; among these, Mre11 and CtIP play essential roles in the initial step of end resection . In contrast to HR, NHEJ is thought to be a rather simpler process that requires, at least biochemically, only four proteins (two protein complexes); specifically, Ku, a heterodimer of Ku70 and Ku80, initiates an NHEJ reaction by binding to the ends of a DSB, and the DNA ligase complex composed of Xrcc4 and Ligase IV (Lig4) seals the ends to complete repair . In most cases, however, many other proteins do participate in NHEJ-mediated repair to trim the DSB ends, which are typically non-ligatable or non-compatible. These additional NHEJ factors involve DNA-PKcs, Artemis, XLF, and DNA polymerase μ/λ; DNA-PKcs and Artemis have evolved in higher eukaryotes and do not exist in yeasts . In addition to the classical pathway of NHEJ, recent evidence indicates the existence of a more error-prone mechanism of NHEJ called alternative endjoining that plays a role in DSB repair . Alternative end-joining is Ku/Lig4 independent and the precise mechanism remains largely unclear, although PARP1, Ligase III, and several factors involved in end resection (to initiate HR) have been implicated in DSB repair via alternative end-joining
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