3 years ago

Genomic rearrangements induced by unscheduled DNA double strand breaks in somatic mammalian cells

Genomic rearrangements induced by unscheduled DNA double strand breaks in somatic mammalian cells
Josée Guirouilh-Barbat, Tangui Le Guen, Bernard S. Lopez, Ayeong So
DNA double-strand breaks (DSBs) are highly toxic lesions that can lead to profound genome rearrangements and/or cell death. They routinely occur in genomes due to endogenous or exogenous stresses. Efficient repair systems, canonical non-homologous end-joining and homologous recombination exist in the cell and not only ensure the maintenance of genome integrity but also, via specific programmed DNA double-strand breaks, permit its diversity and plasticity. However, these repair systems need to be tightly controlled because they can also generate genomic rearrangements. Thus, when DSB repair is not properly regulated, genome integrity is no longer guaranteed. In this review, we will focus on non-programmed genome rearrangements generated by DSB repair, in somatic cells. We first discuss genome rearrangements induced by homologous recombination and end-joining. We then discuss recently described rearrangement mechanisms, driven by microhomologies, that do not involve the joining of DNA ends but rather initiate DNA synthesis (microhomology-mediated break-induced replication, fork stalling and template switching and microhomology-mediated template switching). Finally, we discuss chromothripsis, which is the shattering of a localized region of the genome followed by erratic rejoining. DNA double-strand breaks are highly toxic lesions that routinely occur in genomes, either in physiologically controlled processes, or accidentally due to endogenous or exogenous stresses. Several repair systems exist that guarantee genome integrity but can also generate many kinds of deleterious genomic rearrangements. Here we review genomic rearrangements induced by unscheduled DNA double strand breaks in somatic mammalian cells.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/febs.14053

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