Abstract
Cellular DNA is constantly chemically altered by exogenous and endogenous agents. As all processes of life depend on the transmission of the genetic information, multiple biological processes exist to ensure genome integrity. Chemically damaged DNA has been linked to cancer and aging, therefore it is of great interest to map DNA damage formation and repair to elucidate the distribution of damage on a genome-wide scale. While the low abundance and inability to enzymatically amplify DNA damage are obstacles to genome-wide sequencing, new developments in the last few years have enabled high-resolution mapping of damaged bases. Recently, a number of DNA damage sequencing library construction strategies coupled to new data analysis pipelines allowed the mapping of specific DNA damage formation and repair at high and single nucleotide resolution. Strikingly, these advancements revealed that the distribution of DNA damage is heavily influenced by chromatin states and the binding of transcription factors. In the last seven years, these novel approaches have revealed new genomic maps of DNA damage distribution in a variety of organisms as generated by diverse chemical and physical DNA insults; oxidative stress, chemotherapeutic drugs, environmental pollutants, and sun exposure. Preferred sequences for damage formation and repair have been elucidated, thus making it possible to identify persistent weak spots in the genome as locations predicted to be vulnerable for mutation. As such, sequencing DNA damage will have an immense impact on our ability to elucidate mechanisms of disease initiation, and to evaluate and predict the efficacy of chemotherapeutic drugs.
Highlights
All physiological processes tied to cellular replication rely on the chemical integrity of DNA, and its damage is associated with a range of adverse outcomes such as accelerated aging and cancer.[1,2,3] Endogenous cellular processes and the effects of exogenous agents, including Ultraviolet light (UV) irradiation and chemicals Cecile MingardCecile Mingard received her Master’s degree in Toxicology from the University of Basel in 2016
The more we gain insight into damage distribution both in regards to local sequence context and higher-scale genome arrangement, the better we will be able to link mutational signatures observed in human cancer to their etiological basis in a potentially prognostic manner
This review is useful to consider a broad spectrum of DNA damage sources, both derived from specific chemical modifications, such as carcinogen-DNA adducts, as well as general forms of damage, such as strand breaks, in regards to the state of the art on how to sequence them and emerging biological implications
Summary
All physiological processes tied to cellular replication rely on the chemical integrity of DNA, and its damage is associated with a range of adverse outcomes such as accelerated aging and cancer.[1,2,3] Endogenous cellular processes and the effects of exogenous agents, including UV irradiation and chemicals. Mass spectrometry[12] and 32P-postlabelling[13] allow highsensitivity quantification of total DNA damage in biological samples, but do not provide sequence or location information She completed a PhD (2012) in nucleic acids chemistry at Carleton University. Sturla is the Professor of Toxicology at ETH Zurich She completed her BS and PhD in Chemistry at the University of California at Berkeley and Massachusetts Institute of Technology. LM-PCR can indicate the exact sequence and position of DNA damage on the basis of PCR termination sites; this method is not damage specific, meaning the chemical nature of the damage may be unknown These strategies have various advantages, but do not allow one to relate the chemistry of damage formation with biological changes in particular genes or in the genome. The rapid improvement and adoption of these approaches is expected to spur advances in the study and prevention of aging, cancer, and disease related to genomic instability
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