scholarly journals A Newly Assigned Role of CTCF in Cellular Response to Broken DNAs

Biomolecules ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 363
Author(s):  
Mi Ae Kang ◽  
Jong-Soo Lee
Keyword(s):  
Dna Sequences ◽  
Transcriptional Activation ◽  
Cellular Response ◽  
Developmental Disorders ◽  
Molecular Mechanisms ◽  
Three Dimensional ◽  
Dna Double Strand Breaks ◽  
Dsb Repair ◽  
A Chain

Best known as a transcriptional factor, CCCTC-binding factor (CTCF) is a highly conserved multifunctional DNA-binding protein with 11 zinc fingers. It functions in diverse genomic processes, including transcriptional activation/repression, insulation, genome imprinting and three-dimensional genome organization. A big surprise has recently emerged with the identification of CTCF engaging in the repair of DNA double-strand breaks (DSBs) and in the maintenance of genome fidelity. This discovery now adds a new dimension to the multifaceted attributes of this protein. CTCF facilitates the most accurate DSB repair via homologous recombination (HR) that occurs through an elaborate pathway, which entails a chain of timely assembly/disassembly of various HR-repair complexes and chromatin modifications and coordinates multistep HR processes to faithfully restore the original DNA sequences of broken DNA sites. Understanding the functional crosstalks between CTCF and other HR factors will illuminate the molecular basis of various human diseases that range from developmental disorders to cancer and arise from impaired repair. Such knowledge will also help understand the molecular mechanisms underlying the diverse functions of CTCF in genome biology. In this review, we discuss the recent advances regarding this newly assigned versatile role of CTCF and the mechanism whereby CTCF functions in DSB repair.

PUTRACER: A NOVEL METHOD FOR IDENTIFICATION OF CONTINUOUS-DOMAINS IN MULTI-DOMAIN PROTEINS

2013 ◽  
Vol 11 (01) ◽  
pp. 1340012 ◽  
Author(s):  
SEYED SHAHRIAR ARAB ◽  
MOHAMMADBAGHER PARSA GHARAMALEKI ◽  
ZAIDDODINE PASHANDI ◽  
REZVAN MOBASSERI
Keyword(s):  
Protein Structures ◽  
Three Dimensional ◽  
Accessible Surface Area ◽  
Computer Assisted ◽  
Correct Assignment ◽  
Critical Boundary ◽  
Novel Method ◽  
Accessible Surface ◽  
A Chain

Computer assisted assignment of protein domains is considered as an important issue in structural bioinformatics. The exponential increase in the number of known three dimensional protein structures and the significant role of proteins in biology, medicine and pharmacology illustrate the necessity of a reliable method to automatically detect structural domains as protein units. For this aim, we have developed a program based on the accessible surface area (ASA) and the hydrogen bonds energy in protein backbone (HBE). PUTracer (Protein Unit Tracer) is built on the features of a fast top-down approach to cut a chain into its domains (contiguous domains) with minimal change in ASA as well as HBE. Performance of the program was assessed by a comprehensive benchmark dataset of 124 protein chains, which is based on agreement among experts (e.g. CATH, SCOP) and was expanded to include structures with different types of domain combinations. Equal number of domains and at least 90% agreement in critical boundary accuracy were considered as correct assignment conditions. PUTracer assigned domains correctly in 81.45% of protein chains. Although low critical boundary accuracy in 18.55% of protein chains leads to the incorrect assignments, adjusting the scales causes to improve the performance up to 89.5%. We discuss here the success or failure of adjusting the scales with provided evidences. Availability: PUTracer is available at http://bioinf.modares.ac.ir/software/PUTracer/

scholarly journals Quantitative analysis questions the role of MeCP2 as a global regulator of alternative splicing

2020 ◽  
Author(s):  
Kashyap Chhatbar ◽  
Justyna Cholewa-Waclaw ◽  
Ruth Shah ◽  
Adrian Bird ◽  
Guido Sanguinetti
Keyword(s):  
Alternative Splicing ◽  
Dna Sequences ◽  
Molecular Mechanisms ◽  
Data Sets ◽  
Learning Approaches ◽  
Global Regulator ◽  
Major Function ◽  
Quantitative Analyses ◽  
Different Levels

AbstractMeCP2 is an abundant protein in mature nerve cells, where it binds to DNA sequences containing methylated cytosine. Mutations in the MECP2 gene cause the severe neurological disorder Rett syndrome (RTT), provoking intensive study of the underlying molecular mechanisms. Multiple functions have been proposed, one of which involves a regulatory role in splicing. Here we leverage the recent availability of high-quality transcriptomic data sets to probe quantitatively the potential influence of MeCP2 on alternative splicing. Using a variety of machine learning approaches that can capture both linear and non-linear associations, we show that widely different levels of MeCP2 have a minimal effect on alternative splicing in three different systems. Alternative splicing was also apparently indifferent to developmental changes in DNA methylation levels. Our results suggest that regulation of splicing is not a major function of MeCP2. They also highlight the importance of multi-variate quantitative analyses in the formulation of biological hypotheses.

scholarly journals Structural basis for the coiled-coil architecture of human CtIP

2021 ◽  
Author(s):  
C. R. Morton ◽  
N. J. Rzechorzek ◽  
J. D. Maman ◽  
M. Kuramochi ◽  
H. Sekiguchi ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Three Dimensional ◽  
Coiled Coil ◽  
Strand Break ◽  
Structural Basis ◽  
Binding Motif ◽  
Chromosomal Dna ◽  
Dsb Repair ◽  
Critical Function ◽  
X Ray

AbstractThe DNA repair factor CtIP has a critical function in Double-Strand Break (DSB) repair by Homologous Recombination, promoting the assembly of the repair apparatus at DNA ends and participating in DNA-end resection. However, the molecular mechanisms of CtIP function in DSB repair remain unclear. Here we present an atomic model for the three-dimensional architecture of human CtIP, derived from a multi-disciplinary approach that includes X-ray crystallography, Small-angle X-ray Scattering (SAXS) and Diffracted X-ray Tracking (DXT). Our data show that CtIP adopts an extended dimer-of-dimers structure, in agreement with a role in bridging distant sites on chromosomal DNA during recombinational repair. The zinc-binding motif in CtIP’s N-terminus alters dynamically the coiled coil structure, with functional implications for the long-range interactions of CtIP with DNA. Our results provide a structural basis for the three-dimensional arrangement of chains in the CtIP tetramer, a key aspect of CtIP function in DNA DSB repair.

Homologous chromosome pairing in meiosis of higher eukaryotes—still an enigma?

Genome ◽  
2020 ◽  
Vol 63 (10) ◽  
pp. 469-482
Author(s):  
J. Sybenga
Keyword(s):  
Chromosome Pairing ◽  
Dna Sequences ◽  
Homologous Chromosome ◽  
Homology Search ◽  
Size Difference ◽  
Primary Role ◽  
Dna Double Strand Breaks ◽  
Homologous Chromosome Pairing ◽  
Higher Eukaryotes

Meiosis is the basis of the generative reproduction of eukaryotes. The crucial first step is homologous chromosome pairing. In higher eukaryotes, micrometer-scale chromosomes, micrometer distances apart, are brought together by nanometer DNA sequences, at least a factor of 1000 size difference. Models of homology search, homologue movement, and pairing at the DNA level in higher eukaryotes are primarily based on studies with yeast where the emphasis is on the induction and repair of DNA double-strand breaks (DSB). For such a model, the very large nuclei of most plants and animals present serious problems. Homology search without DSBs cannot be explained by models based on DSB repair. The movement of homologues to meet each other and make contact at the molecular level is not understood. These problems are discussed and the conclusion is that at present practically nothing is known of meiotic homologue pairing in higher eukaryotes up to the formation of the synaptonemal complex, and that new, necessarily speculative models must be developed. Arguments are given that RNA plays a central role in homology search and a tentative model involving RNA in homology search is presented. A role of actin in homologue movement is proposed. The primary role of DSBs in higher eukaryotes is concluded to not be in pairing but in the preparation of Holliday junctions, ultimately leading to chromatid exchange.

scholarly journals DDIT3 (CHOP) contributes to retinal ganglion cell somal loss but not axonal degeneration in DBA/2J mice

2019 ◽  
Vol 5 (1) ◽  
Author(s):  
Olivia J. Marola ◽  
Stephanie B. Syc-Mazurek ◽  
Richard T. Libby
Keyword(s):  
Optic Nerve ◽  
Ocular Hypertension ◽  
Optic Nerve Head ◽  
Cellular Response ◽  
Molecular Mechanisms ◽  
Axonal Degeneration ◽  
Axonal Injury ◽  
Retinal Ganglion ◽  
Age Related

Abstract Glaucoma is an age-related neurodegenerative disease characterized by the progressive loss of retinal ganglion cells (RGCs). Chronic ocular hypertension, an important risk factor for glaucoma, leads to RGC axonal injury at the optic nerve head. This insult triggers molecularly distinct cascades governing RGC somal apoptosis and axonal degeneration. The molecular mechanisms activated by ocular hypertensive insult that drive both RGC somal apoptosis and axonal degeneration are incompletely understood. The cellular response to endoplasmic reticulum stress and induction of pro-apoptotic DNA damage inducible transcript 3 (DDIT3, also known as CHOP) have been implicated as drivers of neurodegeneration in many disease models, including glaucoma. RGCs express DDIT3 after glaucoma-relevant insults, and importantly, DDIT3 has been shown to contribute to both RGC somal apoptosis and axonal degeneration after acute induction of ocular hypertension. However, the role of DDIT3 in RGC somal and axonal degeneration has not been critically tested in a model of age-related chronic ocular hypertension. Here, we investigated the role of DDIT3 in glaucomatous RGC death using an age-related, naturally occurring ocular hypertensive mouse model of glaucoma, DBA/2J mice (D2). To accomplish this, a null allele of Ddit3 was backcrossed onto the D2 background. Homozygous Ddit3 deletion did not alter gross retinal or optic nerve head morphology, nor did it change the ocular hypertensive profile of D2 mice. In D2 mice, Ddit3 deletion conferred mild protection to RGC somas, but did not significantly prevent RGC axonal degeneration. Together, these data suggest that DDIT3 plays a minor role in perpetuating RGC somal apoptosis caused by chronic ocular hypertension-induced axonal injury, but does not significantly contribute to distal axonal degeneration.

scholarly journals Differential activation of target cellular promoters by p53 mutants with impaired apoptotic function.

1996 ◽  
Vol 16 (9) ◽  
pp. 4952-4960 ◽  
Author(s):  
R L Ludwig ◽  
S Bates ◽  
K H Vousden
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Dna Sequences ◽  
Transcriptional Activation ◽  
Cellular Response ◽  
Kinase Inhibitor ◽  
Cell Types ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Cycle Arrest ◽  
P53 Tumor Suppressor Protein

The p53 tumor suppressor protein is a sequence-specific transcriptional activator, a function which contributes to cell cycle arrest and apoptosis induced by p53 in appropriate cell types. Analysis of a series of p53 point mutants has revealed the potential for selective loss of the ability to transactivate some, but not all, cellular p53-responsive promoters. p53 175P and p53 181L are tumor-derived p53 point mutants which were previously characterized as transcriptionally active. Both mutants retained the ability to activate expression of the cyclin-dependent kinase inhibitor p2lcip1/waf1, and this activity correlated with the ability to induce a G1 cell cycle arrest. However, an extension of this survey to include other p53 targets showed that p53 175P was defective in the activation of p53-responsive sequences derived from the bax promoter and the insulin-like growth factor-binding protein 3 gene (IGF-BP3) promoter, while p53 181L showed loss of the ability to activate a promoter containing IGF-BP3 box B sequences. Failure to activate transcription was also reflected in the reduced ability of the mutants to bind the p53-responsive DNA sequences present in these promoters. These specific defects in transcriptional activation correlated with the impaired apoptotic function displayed by these mutants, and the results suggest that activation of cell cycle arrest genes by p53 can be separated from activation of genes with a role in mediating the p53 apoptotic response. The cellular response to p53 activation may therefore depend, at least in part, on which group of p53-responsive genes become transcriptionally activated.

Detecting, signalling and repairing DNA double-strand breaks

2001 ◽  
Vol 29 (6) ◽  
pp. 655-661 ◽  
Author(s):  
S. P. Jackson
Keyword(s):  
Mammalian Cells ◽  
Molecular Mechanisms ◽  
Double Strand Breaks ◽  
Model Organisms ◽  
Dna Double Strand Breaks ◽  
Dsb Repair ◽  
Site Specific ◽  
Strand Breaks ◽  
Dna Dsbs ◽  
Recombination Processes

DNA double-strand breaks (DSBs) can be generated by a variety of genotoxic agents, including ionizing radiation and radiomimetic chemicals. They can also occur when DNA replication complexes encounter other forms of DNA damage, and are produced as intermediates during certain site-specific recombination processes. It is crucial that cells recognize DSBs and bring about their efficient repair, because a single unrepaired cellular DSB can induce cell death, and defective DSB repair can lead to mutations or the loss of significant segments of chromosomal material. Eukaryotic cells have evolved a variety of systems to detect DNA DSBs, repair them, and signal their presence to the transcription, cell cycle and apoptotic machineries. In this review, I describe how work on mammalian cells and also on model organisms such as yeasts has revelaed that such systems are highly conserved throughout evolution, and has provided insights into the molecular mechanisms by which DNA DSBs are recognized, signalled and repaired. I also explain how defects in the proteins that function in these pathways are associated with a variety of human pathological states.

scholarly journals The Role of Drosophila CtIP in Homology-Directed Repair of DNA Double-Strand Breaks

Genes ◽  
2021 ◽  
Vol 12 (9) ◽  
pp. 1430
Author(s):  
Ian Yannuzzi ◽  
Margaret A. Butler ◽  
Joel Fernandez ◽  
Jeannine R. LaRocque
Keyword(s):  
Direct Repeat ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Dsb Repair ◽  
Strand Breaks ◽  
Homology Directed Repair ◽  
Dna End Resection ◽  
The Impact ◽  
End Resection

DNA double-strand breaks (DSBs) are a particularly genotoxic type of DNA damage that can result in chromosomal aberrations. Thus, proper repair of DSBs is essential to maintaining genome integrity. DSBs can be repaired by non-homologous end joining (NHEJ), where ends are processed before joining through ligation. Alternatively, DSBs can be repaired through homology-directed repair, either by homologous recombination (HR) or single-strand annealing (SSA). Both types of homology-directed repair are initiated by DNA end resection. In cultured human cells, the protein CtIP has been shown to play a role in DNA end resection through its interactions with CDK, BRCA1, DNA2, and the MRN complex. To elucidate the role of CtIP in a multicellular context, CRISPR/Cas9 genome editing was used to create a DmCtIPΔ allele in Drosophila melanogaster. Using the DSB repair reporter assay direct repeat of white (DR-white), a two-fold decrease in HR in DmCtIPΔ/Δ mutants was observed when compared to heterozygous controls. However, analysis of HR gene conversion tracts (GCTs) suggests DmCtIP plays a minimal role in determining GCT length. To assess the function of DmCtIP on both short (~550 bp) and long (~3.6 kb) end resection, modified homology-directed SSA repair assays were implemented, resulting in a two-fold decrease in SSA repair in both short and extensive end resection requirements in the DmCtIPΔ/Δ mutants compared to heterozygote controls. Through these analyses, we affirmed the importance of end resection on DSB repair pathway choice in multicellular systems, described the function of DmCtIP in short and extensive DNA end resection, and determined the impact of end resection on GCT length during HR.

scholarly journals Tensor Rules in the Stochastic Organization of Genomes and Genetic Stochastic Resonance in Algebraic Biology

2021 ◽  
Author(s):  
Sergey V. Petoukhov
Keyword(s):  
Quantum Mechanics ◽  
Dna Sequences ◽  
Genomic Dna ◽  
Analytical Tool ◽  
Prokaryotic Genomes ◽  
Algebraic Biology ◽  
Dna Nucleotide Sequence ◽  
A Chain ◽  
Product Of Matrices

The article is devoted to the new results of the author, which add his previously published ones, of studying hidden rules and symmetries in structures of long single-stranded DNA sequences in eukaryotic and prokaryotic genomes. The author uses the existence of different alphabets of n-plets in DNA: the alphabet of 4 nucleotides, the alphabet of 16 douplets, the alphabet of 64 triplets, etc. Each of such DNA alphabets of n-plets can serve for constructing a text as a chain of these n-plets. Using this possibility, the author represents any long DNA nucleotide sequence as a bunch of many so-called n-texts, each of which is written on the basis of one of these alphabets of n-plets. Each of such n-texts has its individual percents of different n-plets in its genomic DNA. But it turns out that in such multi-alphabetical or multilayer presentation of each of many genomic DNA, analyzed by the author, universal rules of probabilities and symmetry exist in interrelations of its different n-texts regarding their percents of n-plets. In this study, the tensor product of matrices and vectors is used as an effective analytical tool borrowed from the arsenal of quantum mechanics. Some additions to the topic of algebra-holographic principles in genetics are also presented. Taking into account the described genomic rules of probability, the author puts also forward a concept of the important role of stochastic resonances in genetic informatics.

scholarly journals Structural basis for the coiled-coil architecture of human CtIP

Open Biology ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 210060
Author(s):  
C. R. Morton ◽  
N. J. Rzechorzek ◽  
J. D. Maman ◽  
M. Kuramochi ◽  
H. Sekiguchi ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Three Dimensional ◽  
Coiled Coil ◽  
Strand Break ◽  
Structural Basis ◽  
Binding Motif ◽  
Chromosomal Dna ◽  
Dsb Repair ◽  
Critical Function ◽  
X Ray

The DNA repair factor CtIP has a critical function in double-strand break (DSB) repair by homologous recombination, promoting the assembly of the repair apparatus at DNA ends and participating in DNA-end resection. However, the molecular mechanisms of CtIP function in DSB repair remain unclear. Here, we present an atomic model for the three-dimensional architecture of human CtIP, derived from a multi-disciplinary approach that includes X-ray crystallography, small-angle X-ray scattering (SAXS) and diffracted X-ray tracking (DXT). Our data show that CtIP adopts an extended dimer-of-dimers structure, in agreement with a role in bridging distant sites on chromosomal DNA during the recombinational repair. The zinc-binding motif in the CtIP N-terminus alters dynamically the coiled-coil structure, with functional implications for the long-range interactions of CtIP with DNA. Our results provide a structural basis for the three-dimensional arrangement of chains in the CtIP tetramer, a key aspect of CtIP function in DNA DSB repair.

Sign in / Sign up

Export Citation Format

Share Document