Topoisomerase-Mediated DNA Damage in Neurological Disorders

Crewe, Morgan; Madabhushi, Ram

doi:10.3389/fnagi.2021.751742

Cited by 10 publications

(10 citation statements)

References 176 publications

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“…In a recent comprehensive study of interactomes of FTO and PCIF1, in addition to their unique partners, both enzymes have protein-interaction networks that include overlapping DNA replication and DNA repair proteins . Among them are DNA helicase RECQ5 with roles in DNA repair and homologous recombination, , a ssDNA-binding protein RADX that is recruited to sites of replication stress to promote genome stability, , DNA double-strand break (DSB) repair enzyme XRCC4, the E3 ubiquitin-protein ligase RNF8 coordinating the repair of DNA lesions in specific chromatin topologies, the tyrosyl DNA phosphodiesterase 2 (TDP2) potentially involved in topoisomerase-mediated DNA damage, or PHRF1, a protein that contains a plant homeodomain (PHD) and a RING domain, possibly promoting genome integrity by modulating non-homologous end-joining . Covelo-Molares et al noted that the identification of proteins involved in DNA replication and repair was the most striking result, with the most enriched and significant FTO interactor being the ssDNA-binding protein RADX …”

Section: Discussionmentioning

confidence: 99%

Enzymatic Characterization of In Vitro Activity of RNA Methyltransferase PCIF1 on DNA

Zhou

Chen

et al. 2022

Biochemistry

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PCIF1 and FTO are a pair of human mRNA cap-specific modification enzymes that have opposing activities. PCIF1 adds a methyl group to the N6-position of 2′ O -methyladenosine (A m ), generating N6, 2′ O -dimethyladenosine (m 6 A m ), when A m is the cap-proximal nucleotide. FTO removes the N6-methyl group from m 6 A m . In addition, FTO has a demethylase activity on a broad spectrum of various RNA substrates, as well as on D NA N6-methyldeoxyadenosine (m 6 dA). While the existence of m 6 dA in mammalian D NA remains controversial, we show here that PCIF1 has significant methylation activity on single stranded DNA deoxyadenosine, double stranded RNA/DNA hybrids, and double stranded DNA, though with lower catalytic efficiency than that on its preferred RNA substrate. PCIF1 has activities in the order ssRNA > RNA/DNA hybrid > ssDNA > dsDNA. We discuss the implications of PCIF1 generation, and FTO removal, of DNA adenine methylation.

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Section: Discussionmentioning

confidence: 99%

Enzymatic Characterization of In Vitro Activity of RNA Methyltransferase PCIF1 on DNA

Zhou

Chen

et al. 2022

Biochemistry

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“…Subsequently, TOP2A as a hub gene of the CCNB2 co-expression module in CIS was found to have the highest mutation frequency, including missense mutation, frameshift insertion mutation, and multihit, in LUAD and LUSC. DNA topoisomerase is the general name of enzymes that can catalyze the conversion of DNA topoisomerase ( Crewe and Madabhushi, 2021 ). TOP2A widely exists in eukaryotic and prokaryotic cells and mainly regulates DNA topology by participating in DNA division, repair, recombination, replication, and transcription ( Di Felice and Camilloni, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Upregulation of CCNB2 and Its Perspective Mechanisms in Cerebral Ischemic Stroke and All Subtypes of Lung Cancer: A Comprehensive Study

Yan

Chen

et al. 2022

Front. Integr. Neurosci.

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Cyclin B2 (CCNB2) belongs to type B cell cycle family protein, which is located on chromosome 15q22, and it binds to cyclin-dependent kinases (CDKs) to regulate their activities. In this study, 103 high-throughput datasets related to all subtypes of lung cancer (LC) and cerebral ischemic stroke (CIS) with the data of CCNB2 expression were collected. The analysis of standard mean deviation (SMD) and summary receiver operating characteristic (SROC) reflecting expression status demonstrated significant up-regulation of CCNB2 in LC and CIS (Lung adenocarcinoma: SMD = 1.40, 95%CI [0.98–1.83], SROC = 0.92, 95%CI [0.89–0.94]. Lung squamous cell carcinoma: SMD = 2.56, 95%CI [1.64–3.48]. SROC = 0.97, 95%CI [0.95–0.98]. Lung small cell carcinoma: SMD = 3.01, 95%CI [2.01–4.01]. SROC = 0.98, 95%CI [0.97–0.99]. CIS: SMD = 0.29, 95%CI [0.05–0.53], SROC = 0.68, 95%CI [0.63–0.71]). Simultaneously, protein-protein interaction (PPI) analysis indicated that CCNB2 is the hub molecule of crossed high-expressed genes in CIS and LC. Through Multiscale embedded gene co-expression network analysis (MEGENA), a gene module of CIS including 76 genes was obtained and function enrichment analysis of the CCNB2 module genes implied that CCNB2 may participate in the processes in the formation of CIS and tissue damage caused by CIS, such as “cell cycle,” “protein kinase activity,” and “glycosphingolipid biosynthesis.” Afterward, via single-cell RNA-seq analysis, CCNB2 was found up-regulated on GABAergic neurons in brain organoids as well as T cells expressing proliferative molecules in LUAD. Concurrently, the expression of CCNB2 distributed similarly to TOP2A as a module marker of cell proliferation in cell cluster. These findings can help in the field of the pathogenesis of LC-related CIS and neuron repair after CIS damage.

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“…Results of several studies suggest that cellular stimulation may cause TOP-mediated DNA breaks (reviewed in Crewe and Madabhushi 2021). The repair of TOP covalent complexes with DNA involves its marking for proteasomal degradation following cleavage of the covalent phosphotyrosyl bond or the adjacent DNA to produce DNA ends for canonical SSBR.…”

Section: Potential Of Aberrant Activity Of Dna Topoisomerases In Migr...mentioning

confidence: 99%

DNA Damage and Repair in Migraine: Oxidative Stress and Beyond

et al. 2022

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Energy generation in the brain to ameliorate energy deficit in migraine leads to oxidative stress as it is associated with reactive oxygen species (ROS) that may damage DNA and show a pronociceptive action in meninges mediated by transient receptor potential cation channel subfamily A member 1 (TRPA1). Recent studies show high levels of single-strand breaks (SSBs) at specific sites in the genome of postmitotic neurons and point at SSB repair (SSBR) as an important element of homeostasis of the central nervous system. DNA topoisomerase 1 (TOP1) is stabilized in the DNA damage-inducing state by neuronal stimulation, including cortical spreading depression. Impairment in poly (ADP-ribose) polymerase 1 (PARP-1) and X-ray repair cross complementing 1 (XRCC1), key SSBR proteins, may be linked with migraine by transient receptor potential melastatin 2 (TRPM2). TRPM2 may also mediate the involvement of migraine-related neuroinflammation with PARP-1 activated by oxidative stress–related SSBs. In conclusion, aberrant activity of SSBR evoked by compromised PARP-1 and XRCC1 may contribute to pathological phenomena in the migraine brain. Such aberrant SSBR results in the lack of repair or misrepair of SSBs induced by ROS or resulting from impaired TOP1. Therefore, components of SSBR may be considered a prospective druggable target in migraine.

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Topoisomerase-Mediated DNA Damage in Neurological Disorders

Cited by 10 publications

References 176 publications

Enzymatic Characterization of In Vitro Activity of RNA Methyltransferase PCIF1 on DNA

Enzymatic Characterization of In Vitro Activity of RNA Methyltransferase PCIF1 on DNA

Upregulation of CCNB2 and Its Perspective Mechanisms in Cerebral Ischemic Stroke and All Subtypes of Lung Cancer: A Comprehensive Study

DNA Damage and Repair in Migraine: Oxidative Stress and Beyond

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