Not breathing is not an option: How to deal with oxidative DNA damage

Oxidative DNA damage constitutes a major threat to genetic integrity, and has thus been implicated in the pathogenesis of a wide variety of diseases, including cancer and neurodegeneration. 7,8-dihydro-8oxo-deoxyGuanine (8-oxo-G) is one of the best characterised oxidative DNA lesions, and it can give rise to point mutations due to its miscoding potential that instructs most DNA polymerases (Pols) to preferentially insert Adenine (A) opposite 8-oxo-G instead of the correct Cytosine (C). If uncorrected, A:8-oxo-G mispairs can give rise to C:G -> A:T transversion mutations. Cells have evolved a variety of pathways to mitigate the mutational potential of 8-oxo-G that include i) mechanisms to avoid incorporation of oxidized nucleotides into DNA through nucleotide pool sanitisation enzymes (by MTH1, MTH2, MTH3 and NUDT5), ii) base excision repair (BER) of 8-oxo-G. in DNA (involving MUTYH, OGG1, Pol lambda, and other components of the BER machinery), and iii) faithful bypass of 8-oxo-G lesions during replication (using a switch between replicative Pols and Pol lambda). In the following, the fate of 8-oxo-G in mammalian cells is reviewed in detail. The differential origins of 8-oxo-G in DNA and its consequences for genetic stability will be covered. This will be followed by a thorough discussion of the different mechanisms in place to cope with 8-oxo-G with an emphasis on Pol lambda-mediated correct bypass of 8-oxo-G during MUTYH-initiated BER as well as replication across 8-oxo-G. Furthermore, the multitude of mechanisms in place to regulate key proteins involved in 8-oxo-G repair will be reviewed. Novel functions of 8-oxo-G as an epigenetic like regulator and insights into the repair of 8-oxo-G within the cellular context will be touched upon. Finally, a discussion will outline the relevance of 8-oxo-G and the proteins involved in dealing with 8-oxo-G to human diseases with a special emphasis on cancer.