scholarly journals NEIL1 and NEIL2 DNA glycosylases modulate anxiety and learning in a cooperative manner in mice

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Gunn A. Hildrestrand ◽  
Veslemøy Rolseth ◽  
Nicolas Kunath ◽  
Rajikala Suganthan ◽  
Vidar Jensen ◽  
...  
Keyword(s):  
Oxidative Dna Damage ◽  
Excision Repair ◽  
Synaptic Function ◽  
Dna Glycosylases ◽  
Ca1 Region ◽  
Hippocampal Ca1 Region ◽  
Dna Base ◽  
Base Excision ◽  
Base Lesion ◽  
The Impact

AbstractOxidative DNA damage in the brain has been implicated in neurodegeneration and cognitive decline. DNA glycosylases initiate base excision repair (BER), the main pathway for oxidative DNA base lesion repair. NEIL1 and NEIL3 DNA glycosylases affect cognition in mice, while the role of NEIL2 remains unclear. Here, we investigate the impact of NEIL2 and its potential overlap with NEIL1 on behavior in knockout mouse models. Neil1−/−Neil2−/− mice display hyperactivity, reduced anxiety and improved learning. Hippocampal oxidative DNA base lesion levels are comparable between genotypes and no mutator phenotype is found. Thus, impaired canonical repair is not likely to explain the altered behavior. Electrophysiology suggests reduced axonal activation in the hippocampal CA1 region in Neil1−/−Neil2−/− mice and lack of NEIL1 and NEIL2 causes dysregulation of genes in CA1 relevant for synaptic function. We postulate a cooperative function of NEIL1 and NEIL2 in genome regulation, beyond canonical BER, modulating behavior in mice.

scholarly journals NEIL1 and NEIL2 DNA glycosylases regulate anxiety and learning in a cooperative manner

2021 ◽  
Author(s):  
Gunn A. Hildrestrand ◽  
Veslemøy Rolseth ◽  
Nicolas Kunath ◽  
Rajikala Suganthan ◽  
Vidar Jensen ◽  
...  
Keyword(s):  
Oxidative Dna Damage ◽  
Excision Repair ◽  
Synaptic Function ◽  
Dna Glycosylases ◽  
Knock Out ◽  
Ca1 Region ◽  
Hippocampal Ca1 Region ◽  
Dna Base ◽  
Base Lesion ◽  
The Impact

AbstractOxidative DNA damage in the brain has been implicated in neurodegeneration and cognitive decline. DNA glycosylases initiate base excision repair (BER), the main pathway for oxidative DNA base lesion repair. NEIL1 and NEIL3 DNA glycosylases alter cognition in mice, the role of NEIL2 remains unclear. Here, we investigate the impact of NEIL2 and its potential overlap with NEIL1 on behavior in single and double knock-out mouse models. Neil1-/-Neil2-/- mice displayed hyperactivity, reduced anxiety and improved learning. Hippocampal oxidative DNA base lesion levels were comparable between genotypes, no mutator phenotype was found. Impaired canonical repair was thus not the cause of altered behavior. Electrophysiology indicated reduced stratum oriens afferents in the hippocampal CA1 region in Neil1-/-Neil2-/-. Within CA1, NEIL1 and NEIL2 jointly regulated transcription in genes relevant for synaptic function. Thus, we postulate a cooperative function of NEIL1 and NEIL2 in genome regulation beyond canonical BER modulating memory formation and anxiety.

Mammalian DNA base excision repair proteins: their interactions and role in repair of oxidative DNA damage

Toxicology ◽  
2003 ◽  
Vol 193 (1-2) ◽  
pp. 43-65 ◽  
Author(s):  
Tadahide Izumi ◽  
Lee R. Wiederhold ◽  
Gargi Roy ◽  
Rabindra Roy ◽  
Arun Jaiswal ◽  
...  
Keyword(s):  
Dna Damage ◽  
Base Excision Repair ◽  
Oxidative Dna Damage ◽  
Excision Repair ◽  
Dna Base Excision Repair ◽  
Dna Base ◽  
Base Excision

scholarly journals Interaction between RECQL4 and OGG1 promotes repair of oxidative base lesion 8-oxoG and is regulated by SIRT1 deacetylase

2020 ◽  
Vol 48 (12) ◽  
pp. 6530-6546 ◽  
Author(s):  
Shunlei Duan ◽  
Xuerui Han ◽  
Mansour Akbari ◽  
Deborah L Croteau ◽  
Lene Juel Rasmussen ◽  
...  
Keyword(s):  
Excision Repair ◽  
Dna Helicase ◽  
Premature Aging ◽  
Major Pathway ◽  
Dna Base ◽  
Dependent Protein ◽  
Rothmund Thomson Syndrome ◽  
Base Excision ◽  
Base Lesion

Abstract OGG1 initiated base excision repair (BER) is the major pathway for repair of oxidative DNA base damage 8-oxoguanine (8-oxoG). Here, we report that RECQL4 DNA helicase, deficient in the cancer-prone and premature aging Rothmund-Thomson syndrome, physically and functionally interacts with OGG1. RECQL4 promotes catalytic activity of OGG1 and RECQL4 deficiency results in defective 8-oxoG repair and increased genomic 8-oxoG. Furthermore, we show that acute oxidative stress leads to increased RECQL4 acetylation and its interaction with OGG1. The NAD+-dependent protein SIRT1 deacetylates RECQL4 in vitro and in cells thereby controlling the interaction between OGG1 and RECQL4 after DNA repair and maintaining RECQL4 in a low acetylated state. Collectively, we find that RECQL4 is involved in 8-oxoG repair through interaction with OGG1, and that SIRT1 indirectly modulates BER of 8-oxoG by controlling RECQL4–OGG1 interaction.

scholarly journals Repair of Oxidative DNA Damage and Cancer: Recent Progress in DNA Base Excision Repair

2014 ◽  
Vol 20 (4) ◽  
pp. 708-726 ◽  
Author(s):  
Timothy L. Scott ◽  
Suganya Rangaswamy ◽  
Christina A. Wicker ◽  
Tadahide Izumi
Keyword(s):  
Dna Damage ◽  
Base Excision Repair ◽  
Recent Progress ◽  
Oxidative Dna Damage ◽  
Excision Repair ◽  
Dna Base Excision Repair ◽  
Dna Base ◽  
Base Excision

scholarly journals Instability of CTG Repeats is Governed by the Position of a DNA Base Lesion through Base Excision Repair

PLoS ONE ◽  
2013 ◽  
Vol 8 (2) ◽  
pp. e56960 ◽  
Author(s):  
Yanhao Lai ◽  
Meng Xu ◽  
Zunzhen Zhang ◽  
Yuan Liu
Keyword(s):  
Base Excision Repair ◽  
Excision Repair ◽  
Ctg Repeats ◽  
Dna Base ◽  
Base Excision ◽  
Base Lesion

scholarly journals Novel method for site-specific induction of oxidative DNA damage reveals differences in recruitment of repair proteins to heterochromatin and euchromatin

2013 ◽  
Vol 42 (4) ◽  
pp. 2330-2345 ◽  
Author(s):  
Li Lan ◽  
Satoshi Nakajima ◽  
Leizhen Wei ◽  
Luxi Sun ◽  
Ching-Lung Hsieh ◽  
...  
Keyword(s):  
Dna Damage ◽  
Oxidative Dna Damage ◽  
Excision Repair ◽  
Dependent Manner ◽  
Dna Glycosylases ◽  
Transcription Activator ◽  
Active Chromatin ◽  
Genomic Locus ◽  
Base Excision ◽  
Protein Recruitment

Abstract Reactive oxygen species (ROS)-induced DNA damage is repaired by the base excision repair pathway. However, the effect of chromatin structure on BER protein recruitment to DNA damage sites in living cells is poorly understood. To address this problem, we developed a method to specifically produce ROS-induced DNA damage by fusing KillerRed (KR), a light-stimulated ROS-inducer, to a tet-repressor (tetR-KR) or a transcription activator (TA-KR). TetR-KR or TA-KR, bound to a TRE cassette (∼90 kb) integrated at a defined genomic locus in U2OS cells, was used to induce ROS damage in hetero- or euchromatin, respectively. We found that DNA glycosylases were efficiently recruited to DNA damage in heterochromatin, as well as in euchromatin. PARP1 was recruited to DNA damage within condensed chromatin more efficiently than in active chromatin. In contrast, recruitment of FEN1 was highly enriched at sites of DNA damage within active chromatin in a PCNA- and transcription activation-dependent manner. These results indicate that oxidative DNA damage is differentially processed within hetero or euchromatin.

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