Abstract
DNA is the source of genetic information, and preserving its integrity is essential in order to sustain life. The genome is continuously threatened by different types of DNA lesions, such as abasic sites, mismatches, interstrand crosslinks, or single-stranded and double-stranded breaks. As a consequence, cells have evolved specialized DNA damage response (DDR) mechanisms to sustain genome integrity. By orchestrating multilayer signaling cascades specific for the type of lesion that occurred, the DDR ensures that genetic information is preserved overtime. In the last decades, DNA repair mechanisms have been thoroughly investigated to untangle these complex networks of pathways and processes. As a result, key factors have been identified that control and coordinate DDR circuits in time and space. In the first part of this review, we describe the critical processes encompassing DNA damage sensing and resolution. In the second part, we illustrate the consequences of partial or complete failure of the DNA repair machinery. Lastly, we will report examples in which this knowledge has been instrumental to develop novel therapies based on genome editing technologies, such as CRISPR-Cas.
Highlights
DNA Lesions as a Constant Threat to the CellDNA harbors the genetic information necessary to build an organism, and its maintenance is pivotal for sustaining life
The most well-documented example is the first clinically approved trial involving the use of designer nucleases to combat infections with the human immunodeficiency virus (HIV), which leads to a disease known as acquired immunodeficiency syndrome (AIDS)
Understanding how genome stability is maintained and investigating the mechanisms adopted by the cells to withstand DNA lesions has been paramount to explore the therapeutic potential of genome editing
Summary
DNA harbors the genetic information necessary to build an organism, and its maintenance is pivotal for sustaining life. Oxygen Species (ROS) or Reactive Nitrogen Species (RNS) are generally produced as byproducts of multiple physiological activities in diverse subcellular sites [4] These chemical compounds are responsible for a variety of DNA lesions derived from oxidative stress, including the generation of apurinic/apyrimidinic sites (AP), single- or double-stranded breaks, and base substitutions [5]. DNA undergoes natural decay processes, such as alkylation, oxidation and deamination, which are mutagenic if not repaired as they lead to incorrect base pairing with consequent base substitutions during DNA replication [8] Another common type of DNA lesion is the single-stranded break (SSB), Cells 2020, 9, 1665; doi:10.3390/cells9071665 www.mdpi.com/journal/cells. Genetic information and genomic stability are constantly threatened by multiple causes and the cells have evolved complex mechanisms to sense, monitor and repair this wide variety of DNA lesions
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