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CHROMOSOMAL STABILITY AND THE DNA DOUBLE-STRANDED BREAK CONNECTION
Dik C. van Gent, Jan H. J. Hoeijmakers and Roland Kanaar*
Genome stability is of primary importance for the survival and proper functioning of all organisms. Double-stranded breaks in DNA are important threats to genome integrity because they can result in chromosomal aberrations that can affect, simultaneously, many genes, and lead to cell malfunctioning and cell death. These detrimental consequences are counteracted by two mechanistically distinct pathways of double-stranded break repair: homologous recombination and non-homologous end-joining. Recently, unexpected links between these double-stranded break-repair systems, and several human genome instability and cancer predisposition syndromes, have emerged. Now, interactions between both double-stranded break-repair pathways and other cellular processes, such as cell-cycle regulation and replication, are being unveiled.
NUCLEOTIDE EXCISION REPAIR
(NER). A DNA-repair pathway that removes ultraviolet-light-induced DNA damage (such as thymidine dimers) and bulky DNA adducts by excising the oligonucleotide that contains the damaged base(s). The single-stranded gap is filled in by using the intact strand as a template.
The faithful maintenance and replication of the genetic instructions that are encrypted in DNA are of primary importance for living organisms. However, damage to DNA is intrinsic to life because its integrity is under constant attack from numerous exogenous agents, including radiation and chemicals, and from endogenous sources, such as free radicals generated during essential metabolic processes. The accumulation of DNA damage can induce permanent changes that lead to cancer or it can lead to severely impaired cellular functioning, which might eventually cause cell death by triggering apoptosis or irreversible cell growth arrest
(FIG. 1). To counteract the deleterious effects of DNA damage, all organisms are equipped with an intricate network of DNA-repair mechanisms that each correct a subset of different lesions. This review focuses on the repair of a particularly genotoxic form of DNA damage the DNA double-stranded break (DSB). These differ from many other types of DNA lesion in that both DNA strands of the double helix are damaged, which prevents the use of the complementary DNA strand as a template for repair. As a result, DSBs can be potent inducers of chromosomal aberrations.
DNA-repair pathways that do use the complementary strand as a template for repair include NUCLEOTIDE
EXCISION REPAIR (NER) and MISMATCH REPAIR (MMR)....