NEIL1 and NEIL2 Are Recruited as Potential Backup for OGG1 upon OGG1 Depletion or Inhibition by TH5487

Abstract

DNA damage caused by reactive oxygen species may result in genetic mutations or cell death. Base excision repair (BER) is the major pathway that repairs DNA oxidative damage in order to maintain genomic integrity. In mammals, eleven DNA glycosylases have been reported to initiate BER, where each recognizes a few related DNA substrate lesions with some degree of overlapping specificity. 7,8-dihydro-8-oxoguanine (8-oxoG), one of the most abundant DNA oxidative lesions, is recognized and excised mainly by 8-oxoguanine DNA glycosylase 1 (OGG1). Further oxidation of 8-oxoG generates hydantoin lesions, which are recognized by NEIL glycosylases. Here, we demonstrate that NEIL1, and to a lesser extent NEIL2, can potentially function as backup BER enzymes for OGG1 upon pharmacological inhibition or depletion of OGG1. NEIL1 recruitment kinetics and chromatin binding after DNA damage induction increase in cells treated with OGG1 inhibitor TH5487 in a dose-dependent manner, whereas NEIL2 accumulation at DNA damage sites is prolonged following OGG1 inhibition. Furthermore, depletion of OGG1 results in increased retention of NEIL1 and NEIL2 at damaged chromatin. Importantly, oxidatively stressed NEIL1- or NEIL2-depleted cells show excessive genomic 8-oxoG lesions accumulation upon OGG1 inhibition, suggesting a prospective compensatory role for NEIL1 and NEIL2. Our study thus exemplifies possible backup mechanisms within the base excision repair pathway.

OGG1 Inhibition Triggers Synthetic Lethality and Enhances The Effect of PARP Inhibitor Olaparib in BRCA1-Deficient TNBC Cells

“…Nevertheless, bearing in mind that knockout mice for Ape1 are embryonic lethal, the treatment with APE1 inhibitors might cause unforeseen on-target toxicities in normal tissues ( 14 ). On the contrary, the deficiency of individual DNA glycosylases, which initiate BER, is relatively well-tolerated, and therefore these enzymes may be more promising candidates for drug development ( 14 , 16 , 18 , 19 ). In particular, it has been described that the knockdown of OGG1 conferred sensitivity to PARP1 inhibition ( 20 , 21 ).…”

Biological Functions of the DNA Glycosylase NEIL3 and Its Role in Disease Progression Including Cancer

“…NTH1 and OGG1 are active only on double-stranded DNA, cleaving mainly oxidized pyrimidines and purines [ 15 , 21 , 22 ]. A study confirmed that 8-oxoG was mainly recognized and excised by OGG1, and when OGG1 was depleted or inhibited, NEIL1 and NEIL2 aggregated at sites of 8-oxoG damage as backup BER enzymes that complemented OGG1 [ 23 ]. NEIL1 and NEIL2 remove damaged bases from not only double-stranded DNA (dsDNA) and single-stranded DNA (ssDNA), but also remove 5-OHU damage in DNA bubbles [ 21 , 24 ].…”

OGG1 contributes to hepatocellular carcinoma by promoting cell cycle‐related protein expression and enhancing DNA oxidative damage repair in tumor cells

“…38 It was also reported that the upregulation of CCNB1 in primary liver cancer might be a potential biomarker to evaluate the prognosis of HCC. 39 In recent years, there was growing evidence suggesting that OGG1, in addition to DNA repair, played an epigenetic regulation role in transcription, 40 which could promote transcription of oncogene like c-Myc and inflammatory factors like CXCL1 and TNFα. 41,42 In summary, OGG1 was highly expressed in HCC patients and was related to the grading, staging, and prognosis of HCC, which could be used as a potential biomarker for HCC.…”