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DNA glycosylase NEIL2 functions in multiple cellular processes.

ABSTRACT: Cell survival largely depends on the faithful maintenance of genetic material since genomic DNA is constantly exposed to genotoxicants from both endogenous and exogenous sources. The evolutionarily conserved base excision repair (BER) pathway is critical for maintaining genome integrity by eliminating highly abundant and potentially mutagenic oxidized DNA base lesions. BER is a multistep process, which is initiated with recognition and excision of the DNA base lesion by a DNA glycosylase, followed by DNA end processing, gap filling and finally sealing of the nick. Besides genome maintenance by global BER, DNA glycosylases have been found to play additional roles, including preferential repair of oxidized lesions from transcribed genes, modulation of the immune response, participation in active DNA demethylation and maintenance of the mitochondrial genome. Central to these functions is the DNA glycosylase NEIL2. Its loss results in increased accumulation of oxidized base lesions in the transcribed genome, triggers an immune response and causes early neurodevelopmental defects, thus emphasizing the multitasking capabilities of this repair protein. Here we review the specialized functions of NEIL2 and discuss the consequences of its absence both in vitro and in vivo.

SUBMITTER: Sarker AH

PROVIDER: S-EPMC10277195 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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DNA glycosylase NEIL2 functions in multiple cellular processes.

Sarker Altaf H AH Cooper Priscilla K PK Hazra Tapas K TK

Progress in biophysics and molecular biology 20210320

Cell survival largely depends on the faithful maintenance of genetic material since genomic DNA is constantly exposed to genotoxicants from both endogenous and exogenous sources. The evolutionarily conserved base excision repair (BER) pathway is critical for maintaining genome integrity by eliminating highly abundant and potentially mutagenic oxidized DNA base lesions. BER is a multistep process, which is initiated with recognition and excision of the DNA base lesion by a DNA glycosylase, follow ...[more]

PMID: 33753087

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Project description:Reactive oxygen species (ROS) generated endogenously or from exogenous sources produce mutagenic DNA lesions. If not repaired, these lesions could lead to genomic instability and, potentially, to cancer development. NEIL2 (EC 4.2.99.18), a mammalian base excision repair (BER) protein and ortholog of the bacterial Fpg/Nei, excises oxidized DNA lesions from bubble or single-stranded structures, suggesting its involvement in transcription-coupled DNA repair. Perturbation in NEIL2 expression may, therefore, significantly impact BER capacity and promote genomic instability. To characterize the genetic and environmental factors regulating NEIL2 gene expression, we mapped the human NEIL2 transcriptional start site and partially characterized the promoter region of the gene using a luciferase reporter assay. We identified a strong positive regulatory region from nucleotide -206 to +90 and found that expression from this region was contingent on its being isolated from an adjacent strong negative regulatory region located downstream (+49 to +710 bp), suggesting that NEIL2 transcription is influenced by both these regions. We also found that oxidative stress, induced by glucose oxidase treatment, reduced the positive regulatory region expression levels, suggesting that ROS may play a significant role in regulating NEIL2 transcription. In an initial attempt to characterize the underlying mechanisms, we used in silico analysis to identify putative cis-acting binding sites for ROS-responsive transcription factors within this region and then used site-directed mutagenesis to investigate their role. A single-base change in the region encompassing nucleotides -206 to +90 abolished the effect of oxidative stress that was observed in the absence of the mutation. Our study is the first to provide an initial partial characterization of the NEIL2 promoter and opens the door for future research aimed at understanding the role of genetic and environmental factors in regulating NEIL2 expression.

Dataset Information

DNA glycosylase NEIL2 functions in multiple cellular processes.

Publications

DNA glycosylase NEIL2 functions in multiple cellular processes.

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