scholarly journals Cooperation of the NEIL3 and Fanconi anemia/BRCA pathways in interstrand crosslink repair

2020 ◽  
Vol 48 (6) ◽  
pp. 3014-3028 ◽  
Author(s):  
Niu Li ◽  
Jian Wang ◽  
Susan S Wallace ◽  
Jing Chen ◽  
Jia Zhou ◽  
...  
Keyword(s):  
Fanconi Anemia ◽  
Excision Repair ◽  
Human Cells ◽  
Dependent Manner ◽  
Major Pathway ◽  
Interstrand Crosslinks ◽  
Interstrand Crosslink ◽  
Pathway Activation ◽  
Base Excision ◽  
And Function

Abstract The NEIL3 DNA glycosylase is a base excision repair enzyme that excises bulky base lesions from DNA. Although NEIL3 has been shown to unhook interstrand crosslinks (ICL) in Xenopus extracts, how NEIL3 participants in ICL repair in human cells and its corporation with the canonical Fanconi anemia (FA)/BRCA pathway remain unclear. Here we show that the NEIL3 and the FA/BRCA pathways are non-epistatic in psoralen-ICL repair. The NEIL3 pathway is the major pathway for repairing psoralen-ICL, and the FA/BRCA pathway is only activated when NEIL3 is not present. Mechanistically, NEIL3 is recruited to psoralen-ICL in a rapid, PARP-dependent manner. Importantly, the NEIL3 pathway repairs psoralen-ICLs without generating double-strand breaks (DSBs), unlike the FA/BRCA pathway. In addition, we found that the RUVBL1/2 complex physically interact with NEIL3 and function within the NEIL3 pathway in psoralen-ICL repair. Moreover, TRAIP is important for the recruitment of NEIL3 but not FANCD2, and knockdown of TRAIP promotes FA/BRCA pathway activation. Interestingly, TRAIP is non-epistatic with both NEIL3 and FA pathways in psoralen-ICL repair, suggesting that TRAIP may function upstream of the two pathways. Taken together, the NEIL3 pathway is the major pathway to repair psoralen-ICL through a unique DSB-free mechanism in human cells.

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

2021 ◽  
Vol 22 (9) ◽  
pp. 4542
Author(s):  
Bishoy M. F. Hanna ◽  
Maurice Michel ◽  
Thomas Helleday ◽  
Oliver Mortusewicz
Keyword(s):  
Dna Damage ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Dependent Manner ◽  
Chromatin Binding ◽  
Dna Glycosylases ◽  
Major Pathway ◽  
Base Excision ◽  
Dose Dependent ◽  
Dna Substrate

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.

Base excision repair of DNA in γ-irradiated human cells

1987 ◽  
Vol 8 (4) ◽  
pp. 607-609 ◽  
Author(s):  
Michael F. Moran ◽  
Kaney Ebisuzaki
Keyword(s):  
Base Excision Repair ◽  
Excision Repair ◽  
Human Cells ◽  
Base Excision

scholarly journals DNA Oxidation and Excision Repair Pathways

2019 ◽  
Vol 20 (23) ◽  
pp. 6092 ◽  
Author(s):  
Tae-Hee Lee ◽  
Tae-Hong Kang
Keyword(s):  
Genomic Dna ◽  
Cancer Susceptibility ◽  
Excision Repair ◽  
Dna Oxidation ◽  
Oxidation Products ◽  
Loss Of Function ◽  
Major Pathway ◽  
Repair Pathways ◽  
Lesion Recognition ◽  
Base Excision

The physiological impact of the aberrant oxidation products on genomic DNA were demonstrated by embryonic lethality or the cancer susceptibility and/or neurological symptoms of animal impaired in the base excision repair (BER); the major pathway to maintain genomic integrity against non-bulky DNA oxidation. However, growing evidence suggests that other DNA repair pathways or factors that are not primarily associated with the classical BER pathway are also actively involved in the mitigation of oxidative assaults on the genomic DNA, according to the corresponding types of DNA oxidation. Among others, factors dedicated to lesion recognition in the nucleotide excision repair (NER) pathway have been shown to play eminent roles in the process of lesion recognition and stimulation of the enzyme activity of some sets of BER factors. Besides, substantial bulky DNA oxidation can be preferentially removed by a canonical NER mechanism; therefore, loss of function in the NER pathway shares common features arising from BER defects, including cancer predisposition and neurological disorders, although NER defects generally are nonlethal. Here we discuss recent achievements for delineating newly arising roles of NER lesion recognition factors to facilitate the BER process, and cooperative works of BER and NER pathways in response to the genotoxic oxidative stress.

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 Coordinated Cut and Bypass: Replication of Interstrand Crosslink-Containing DNA

2021 ◽  
Vol 9 ◽  
Author(s):  
Qiuzhen Li ◽  
Kata Dudás ◽  
Gabriella Tick ◽  
Lajos Haracska
Keyword(s):  
Dna Replication ◽  
Fanconi Anemia ◽  
Replication Fork ◽  
Defense Mechanism ◽  
Genome Instability ◽  
Dna Lesions ◽  
Fanconi Anemia Pathway ◽  
Interstrand Crosslinks ◽  
Dna Lesion ◽  
Interstrand Crosslink

DNA interstrand crosslinks (ICLs) are covalently bound DNA lesions, which are commonly induced by chemotherapeutic drugs, such as cisplatin and mitomycin C or endogenous byproducts of metabolic processes. This type of DNA lesion can block ongoing RNA transcription and DNA replication and thus cause genome instability and cancer. Several cellular defense mechanism, such as the Fanconi anemia pathway have developed to ensure accurate repair and DNA replication when ICLs are present. Various structure-specific nucleases and translesion synthesis (TLS) polymerases have come into focus in relation to ICL bypass. Current models propose that a structure-specific nuclease incision is needed to unhook the ICL from the replication fork, followed by the activity of a low-fidelity TLS polymerase enabling replication through the unhooked ICL adduct. This review focuses on how, in parallel with the Fanconi anemia pathway, PCNA interactions and ICL-induced PCNA ubiquitylation regulate the recruitment, substrate specificity, activity, and coordinated action of certain nucleases and TLS polymerases in the execution of stalled replication fork rescue via ICL bypass.

scholarly journals Single-cell transcriptome reveals a testis-specific expression profile of TCEA in human spermatogenesis

2021 ◽  
Author(s):  
S. Pankaew ◽  
P. Pramoj Na Ayutthaya
Keyword(s):  
Rna Polymerase Ii ◽  
Gene Transcription ◽  
Expression Profile ◽  
Excision Repair ◽  
Elongation Factor ◽  
Specific Expression ◽  
Major Pathway ◽  
Base Excision ◽  
Human Spermatogenesis ◽  
Transcriptional Bursting

AbstractTranscription elongation factor A (TCEA) is a eukaryotic transcriptional molecule, required for a formation of initiation and elongation of gene transcription-mediated RNA polymerase II (RNAPII) complex, to promote transcription-coupled nucleotide excision repair (TC-NER) after RNAPII backtracking recovery. TCEA shares three isoforms in which TCEA1 is ubiquitously expressed among all eukaryotic cells. We found a spermatogenesis TCEA1 and TCEA2 expression profile has a unique transcriptional programme, compared with embryogenesis. Moreover, the testis-specific TCEA2 profile correlates with gene transcription, whereas TCEA1 specifically correlates with genes transcribed for Nuclear excision repair (NER) during human spermatogenesis. We also found that the expression activation of RNF20, a TCEA1 inhibitor, leads to expressional TCEA1 reduction, but having no direct impact on TCEA2 expression, implying the potential RNF20-dependent transcriptional switching of TCEA2 in transcriptional regulation during spermatogenesis. Our analysis defined a transcriptional bursting event where transcription-coupled repair (both Base excision repair and Nuclear excision repair) is a major pathway highly expressed in early spermatogenesis, supporting the transcriptional scanning hypothesis of which mutation of transcribed genes is effectively repaired as proposed by Xia B., et al. (2020).

scholarly journals The Response to Oxidative DNA Damage in Neurons: Mechanisms and Disease

2016 ◽  
Vol 2016 ◽  
pp. 1-14 ◽  
Author(s):  
Laura Narciso ◽  
Eleonora Parlanti ◽  
Mauro Racaniello ◽  
Valeria Simonelli ◽  
Alessio Cardinale ◽  
...  
Keyword(s):  
Dna Damage ◽  
Genome Stability ◽  
Oxidative Dna Damage ◽  
Excision Repair ◽  
Strand Breaks ◽  
Single Strand Breaks ◽  
Age Related ◽  
Neurological Alterations ◽  
Base Excision ◽  
And Function

There is a growing body of evidence indicating that the mechanisms that control genome stability are of key importance in the development and function of the nervous system. The major threat for neurons is oxidative DNA damage, which is repaired by the base excision repair (BER) pathway. Functional mutations of enzymes that are involved in the processing of single-strand breaks (SSB) that are generated during BER have been causally associated with syndromes that present important neurological alterations and cognitive decline. In this review, the plasticity of BER during neurogenesis and the importance of an efficient BER for correct brain function will be specifically addressed paying particular attention to the brain region and neuron-selectivity in SSB repair-associated neurological syndromes and age-related neurodegenerative diseases.

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