Cooperation and interplay between base and nucleotide excision repair pathways: From DNA lesions to proteins

Namrata Kumar,Carlos Fm Menck,Natália C Moreno,Bennett Van Houten,Bruno C Feltes

doi:10.1590/1678-4685-gmb-2019-0104

Abstract

Base and nucleotide excision repair (BER and NER) pathways are normally associated with removal of specific types of DNA damage: small base modifications (such as those induced by DNA oxidation) and bulky DNA lesions (such as those induced by ultraviolet or chemical carcinogens), respectively. However, growing evidence indicates that this scenario is much more complex and these pathways exchange proteins and cooperate with each other in the repair of specific lesions. In this review, we highlight studies discussing the involvement of NER in the repair of DNA damage induced by oxidative stress, and BER participating in the removal of bulky adducts on DNA. Adding to this complexity, UVA light experiments revealed that oxidative stress also causes protein oxidation, directly affecting proteins involved in both NER and BER. This reduces the cell’s ability to repair DNA damage with deleterious implications to the cells, such as mutagenesis and cell death, and to the organisms, such as cancer and aging. Finally, an interactome of NER and BER proteins is presented, showing the strong connection between these pathways, indicating that further investigation may reveal new functions shared by them, and their cooperation in maintaining genome stability.

Highlights

It has been suggested that every cell in our body suffers tens of thousands of lesions per day (Lindahl and Barnes, 2000; Tubbs and Nussenzweig, 2017), which if left unrepaired, may lead to mutations, genome instability and cancer
As for other DNA repair pathways, proteins that participate in nucleotide excision repair (NER) and base excision repair (BER) are subject to injury, mainly by oxidation, an effect that has been little explored
During repair this gap is filled in by DNA polymerase beta, and ligated by DNA ligase I or III. While both BER and NER pathways have been conventionally associated with specific substrates, growing evidence shows a significant cooperation between these two repair mechanisms, and has recently been reviewed (Melis et al, 2013; Limpose et al, 2017; Shafirovich and Geacintov, 2017). The relevance of this potential interaction includes the fact that NER deficient (XP and Cockayne syndrome (CS)) patients may develop developmental and neurological symptoms, related to premature aging, that can be due to endogenous lesions, such as DNA damage induced by oxidation, which are normally considered substrates for BER

Summary

Introduction

It has been suggested that every cell in our body suffers tens of thousands of lesions per day (Lindahl and Barnes, 2000; Tubbs and Nussenzweig, 2017), which if left unrepaired, may lead to mutations, genome instability and cancer. The relevance of this potential interaction includes the fact that NER deficient (XP and CS) patients may develop developmental and neurological symptoms, related to premature aging, that can be due to endogenous lesions, such as DNA damage induced by oxidation, which are normally considered substrates for BER.

Results

Conclusion