(5′S) 5′,8-cyclo-2′-deoxyadenosine Cannot Stop BER. Clustered DNA Lesion Studies

As a result of external and endocellular physical-chemical factors, every day approximately similar to 10(5) DNA lesions might be formed in each human cell. During evolution, living organisms have developed numerous repair systems, of which Base Excision Repair (BER) is the most common. 5',8-cyclo-2'-deoxyadenosine (cdA) is a tandem lesion that is removed by the Nucleotide Excision Repair (NER) mechanism. Previously, it was assumed that BER machinery was not able to remove (5'S)cdA from the genome. In this study; however, it has been demonstrated that, if (5'S)cdA is a part of a single-stranded clustered DNA lesion, it can be removed from ds-DNA by BER. The above is theoretically possible in two cases: (A) When, during repair, clustered lesions form Okazaki-like fragments; or (B) when the (5'S)cdA moiety is located in the oligonucleotide strand on the 3-end side of the adjacent DNA damage site, but not when it appears at the opposite 5-end side. To explain this phenomenon, pure enzymes involved in BER were used (polymerase beta (Pol beta), a Proliferating Cell Nuclear Antigen (PCNA), and the X-Ray Repair Cross-Complementing Protein 1 (XRCC1)), as well as the Nuclear Extract (NE) from xrs5 cells. It has been found that Pol beta can effectively elongate the primer strand in the presence of XRCC1 or PCNA. Moreover, supplementation of the NE from xrs5 cells with Pol beta (artificial Pol beta overexpression) forced oligonucleotide repair via BER in all the discussed cases.

Automated summary

Every day, a large number of DNA lesions are formed in cells due to various factors, and Base Excision Repair is a common repair mechanism. Research has shown that a specific DNA lesion previously thought to be unrepairable can actually be removed under certain conditions, shedding light on new possibilities for DNA damage repair.