scholarly journals Interstrand Crosslink Repair: New Horizons of DNA Damage Repair

2021 ◽  
Author(s):  
Amna Aqeel ◽  
Javaria Zafar ◽  
Naureen Ehsan ◽  
Qurat-Ul-Ain ◽  
Mahnoor Tariq ◽  
...  
Keyword(s):  
Fanconi Anemia ◽  
Well Being ◽  
Chemotherapeutic Agents ◽  
New Horizons ◽  
Interstrand Crosslinks ◽  
Interstrand Crosslink ◽  
Damage Repair ◽  
Repair Mechanisms ◽  
Hereditary Disorders ◽  
Living Organisms

Since the dawn of civilization, living organisms are unceasingly exposed to myriads of DNA damaging agents that can temper the ailments and negatively influence the well-being. DNA interstrand crosslinks (ICLs) are spawned by various endogenous and chemotherapeutic agents, thus posing a somber menace to genome solidity and cell endurance. However, the robust techniques of damage repair including Fanconi anemia pathway, translesion synthesis, nucleotide excision and homologous recombination repair faithfully protect the DNA by removing or tolerating damage to ensure the overall survival. Aberrations in such repair mechanisms adverse the pathophysiological states of several hereditary disorders i.e. Fanconi Anemia, xeroderma pigmentosum, cerebro-oculo-facio-skeletal syndrome and cockayne syndrome etc. Although, the recognition of ICL lesions during interphase have opened the new horizons of research in the field of genetics but still the detailed analysis of conditions in which repair should occur is largely elusive.

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 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 EXD2 and WRN exonucleases are required for interstrand crosslink repair in Drosophila

2018 ◽  
Author(s):  
Pratima Chennuri ◽  
Lynne S. Cox ◽  
Robert D. C. Saunders
Keyword(s):  
Genomic Instability ◽  
Fanconi Anemia ◽  
Werner Syndrome ◽  
Fruit Fly ◽  
Chromosome Breakage ◽  
Cancer Therapies ◽  
Principal Mechanism ◽  
Interstrand Crosslinks ◽  
Interstrand Crosslink ◽  
Interstrand Crosslink Repair

AbstractInterstrand crosslinks (ICLs) present a major threat to genome integrity, preventing both the correct transcription of active chromatin and complete replication of the genome. This is exploited in genotoxic chemotherapy where ICL induction is used to kill highly proliferative cancer cells. Repair of ICLs involves a complex interplay of numerous proteins, including those in the Fanconi anemia (FA) pathway, though alternative and parallel pathways have been postulated. Here, we investigate the role of the 3’-5’ exonuclease, EXD2, and the highly related WRN exonuclease (implicated in premature ageing human Werner syndrome), in repair of interstrand crosslinks in the fruit fly, Drosophila melanogaster. We find that flies mutant for EXD2 (DmEXD2) have elevated rates of genomic instability resulting from chromosome breakage and loss of the resulting acentric fragments, in contrast to WRN exonuclease (DmWRNexo) mutants where excess homologous recombination is the principal mechanism of genomic instability. Most notably, we demonstrate that proliferating larval neuroblasts mutant for either DmWRNexo or DmEXD2 are deficient in repair of DNA interstrand crosslinks caused by diepoxybutane or mitomycin C, strongly suggesting that each nuclease individually plays a role in repair of ICLs in flies. These findings have significant implications not only for understanding the complex process of ICL repair in humans, but also for enhancing cancer therapies that rely on ICL induction, with caveats for cancer therapy in Werner syndrome and Fanconi anemia patients.

Narrative as active inference

2020 ◽  
Author(s):  
Nabil Bouizegarene ◽  
maxwell ramstead ◽  
Axel Constant ◽  
Karl Friston ◽  
Laurence Kirmayer
Keyword(s):  
Well Being ◽  
Social Practices ◽  
Human Adaptation ◽  
Active Inference ◽  
Future Projection ◽  
Future Developments ◽  
The Social ◽  
Parsimonious Model ◽  
Living Organisms ◽  
Theory Research

The ubiquity and importance of narratives in human adaptation has been recognized by many scholars. Research has identified several functions of narratives that are conducive to individuals’ well-being and adaptation as well as to coordinated social practices and enculturation. In this paper, we characterize the social and cognitive functions of narratives in terms of the framework of active inference. Active inference depicts the fundamental tendency of living organisms to adapt by creating, updating, and maintaining inferences about their environment. We review the literature on the functions of narratives in identity, event segmentation, episodic memory, future projection, storytelling practices, and enculturation. We then re-cast these functions of narratives in terms of active inference, outlining a parsimonious model that can guide future developments in narrative theory, research, and clinical applications.

scholarly journals Regulatory and Functional Involvement of Long Non-Coding RNAs in DNA Double-Strand Break Repair Mechanisms

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1506
Author(s):  
Angelos Papaspyropoulos ◽  
Nefeli Lagopati ◽  
Ioanna Mourkioti ◽  
Andriani Angelopoulou ◽  
Spyridon Kyriazis ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Strand Break ◽  
Dna Double Strand Breaks ◽  
End Joining ◽  
Dsb Repair ◽  
Repair Mechanisms ◽  
Non Coding Rnas ◽  
Repair Pathways ◽  
Non Homologous End Joining ◽  
Living Organisms

Protection of genome integrity is vital for all living organisms, particularly when DNA double-strand breaks (DSBs) occur. Eukaryotes have developed two main pathways, namely Non-Homologous End Joining (NHEJ) and Homologous Recombination (HR), to repair DSBs. While most of the current research is focused on the role of key protein players in the functional regulation of DSB repair pathways, accumulating evidence has uncovered a novel class of regulating factors termed non-coding RNAs. Non-coding RNAs have been found to hold a pivotal role in the activation of DSB repair mechanisms, thereby safeguarding genomic stability. In particular, long non-coding RNAs (lncRNAs) have begun to emerge as new players with vast therapeutic potential. This review summarizes important advances in the field of lncRNAs, including characterization of recently identified lncRNAs, and their implication in DSB repair pathways in the context of tumorigenesis.

scholarly journals The Fanconi anemia DNA damage repair pathway in the spotlight for germline predisposition to colorectal cancer

2016 ◽  
Vol 24 (10) ◽  
pp. 1501-1505 ◽  
Author(s):  
Clara Esteban-Jurado ◽  
◽  
Sebastià Franch-Expósito ◽  
Jenifer Muñoz ◽  
Teresa Ocaña ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Damage ◽  
Fanconi Anemia ◽  
Dna Damage Repair ◽  
Repair Pathway ◽  
Damage Repair

scholarly journals Expression of DNA repair and metabolic genes in response to a flavonoid-rich diet

2007 ◽  
Vol 98 (3) ◽  
pp. 525-533 ◽  
Author(s):  
Simonetta Guarrera ◽  
Carlotta Sacerdote ◽  
Laura Fiorini ◽  
Rosa Marsala ◽  
Silvia Polidoro ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Repair ◽  
Significant Negative Correlation ◽  
Dna Repair Genes ◽  
Metabolic Genes ◽  
Damage Repair ◽  
Flavonoid Intake ◽  
Repair Mechanisms ◽  
Repair Genes

A diet rich in fruit and vegetables can be effective in the reduction of oxidative stress, through the antioxidant effects of phytochemicals and other mechanisms. Protection against the carcinogenic effects of chemicals may also be exerted by an enhancement of detoxification and DNA damage repair mechanisms. To investigate a putative effect of flavonoids, a class of polyphenols, on the regulation of the gene expression of DNA repair and metabolic genes, a 1-month flavonoid-rich diet was administered to thirty healthy male smokers, nine of whom underwent gene expression analysis. We postulated that tobacco smoke is a powerful source of reactive oxygen species. The expression level of twelve genes (APEX, ERCC1, ERCC2, ERCC4, MGMT, OGG1, XPA, XPC, XRCC1, XRCC3, AHR, CYP1A1) was investigated. We found a significant increase (P < 0·001) in flavonoid intake. Urinary phenolic content and anti-mutagenicity did not significantly change after diet, nor was a correlation found between flavonoid intake and urinary phenolic levels or anti-mutagenicity. Phenolic levels showed a significant positive correlation with urinary anti-mutagenicity. AHR levels were significantly reduced after the diet (P = 0·038), whereas the other genes showed a generalized up regulation, significant for XRCC3 gene (P = 0·038). Also in the context of a generalized up regulation of DNA repair genes, we found a non-significant negative correlation between flavonoid intake and the expression of all the DNA repair genes. Larger studies are needed to clarify the possible effects of flavonoids in vivo; our preliminary results could help to better plan new studies on gene expression and diet.

scholarly journals The emerging role of RNAs in DNA damage repair

2017 ◽  
Vol 24 (4) ◽  
pp. 580-587 ◽  
Author(s):  
Ben R Hawley ◽  
Wei-Ting Lu ◽  
Ania Wilczynska ◽  
Martin Bushell
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Critical Role ◽  
Repair Process ◽  
Rna Molecules ◽  
Processing Enzymes ◽  
Damage Repair ◽  
New Findings ◽  
Integral Role ◽  
Repair Mechanisms

Abstract Many surveillance and repair mechanisms exist to maintain the integrity of our genome. All of the pathways described to date are controlled exclusively by proteins, which through their enzymatic activities identify breaks, propagate the damage signal, recruit further protein factors and ultimately resolve the break with little to no loss of genetic information. RNA is known to have an integral role in many cellular pathways, but, until very recently, was not considered to take part in the DNA repair process. Several reports demonstrated a conserved critical role for RNA-processing enzymes and RNA molecules in DNA repair, but the biogenesis of these damage-related RNAs and their mechanisms of action remain unknown. We will explore how these new findings challenge the idea of proteins being the sole participants in the response to DNA damage and reveal a new and exciting aspect of both DNA repair and RNA biology.

scholarly journals Differential functions of FANCI and FANCD2 ubiquitination stabilize ID2 complex on DNA

2020 ◽  
Author(s):  
Martin L. Rennie ◽  
Kimon Lemonidis ◽  
Connor Arkinson ◽  
Viduth K. Chaugule ◽  
Mairi Clarke ◽  
...  
Keyword(s):  
Fanconi Anemia ◽  
Large Scale ◽  
The Other ◽  
Molecular Function ◽  
Post Translational Modifications ◽  
Hydrophobic Residues ◽  
Interstrand Crosslinks ◽  
Double Stranded Dna ◽  
Dna Interstrand Crosslinks ◽  
Lysine Residues

AbstractThe Fanconi Anemia (FA) pathway is a dedicated pathway for the repair of DNA interstrand crosslinks, and which is additionally activated in response to other forms of replication stress. A key step in the activation of the FA pathway is the monoubiquitination of each of the two subunits (FANCI and FANCD2) of the ID2 complex on specific lysine residues. However, the molecular function of these modifications has been unknown for nearly two decades. Here we find that ubiquitination of FANCD2 acts to increase ID2’s affinity for double stranded DNA via promoting/stabilizing a large-scale conformational change in the complex, resulting in a secondary “Arm” ID2 interphase encircling DNA. Ubiquitination of FANCI, on the other hand, largely protects the ubiquitin on FANCD2 from USP1/UAF deubiquitination, with key hydrophobic residues of FANCI’s ubiquitin being important for this protection. In effect, both of these post-translational modifications function to stabilise a conformation in which the ID2 complex encircles DNA.

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