JournalTOCs

Genome Instability & Disease
Number of Followers: 0

Hybrid journal (It can contain Open Access articles)
ISSN (Online) 2524-7662
Published by Springer-Verlag

[2469 journals]

DNA-PKcs post-translational modifications and associated diseases
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  Abstract: Abstract DNA-dependent protein kinase catalytic subunit (DNA-PKcs) forms DNA-PK holoenzyme with Ku70/Ku80 heterodimer, which initiates the (non-homologous end-joining) NHEJ repair upon double-strand breaks (DSBs). Besides function in NHEJ, DNA-PKcs also plays multiple roles in other biological processes including transcription, telomere maintenance, autophagy, cell cycle checkpoint, and lymphocyte development. Dysregulation of DNA-PKcs associates with various diseases such as genome instability and cancer, immunological deficiency, and neurological disorders. DNA-PKcs function is strictly controlled by post-translational modifications, especially phosphorylation. DNA-PKcs phosphorylation affects either the end-processing or the end-joining in DSB repair or Variable (V) Diversity (D) and Joining (J)/Class switch recombination in lymphocytes development. With increasing evidence of proteomic advances in DNA-PKcs study, other PTMs have been added including ubiquitination, neddylation, acetylation, and PARylation. Different DNA-PKcs PTMs may be involved different pathophysiological activities. Moreover, complexed crosstalk between DNA-PKcs phosphorylation and other PTMs will further aid the understanding of DNA-PKcs biology.
  PubDate: 2022-04-28
The impact of TOPBP1 mutations in human cancers on the DNA damage response
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  Abstract: Abstract TOPBP1 (Topoisomerase IIβ-binding protein 1) mediates protein–protein interaction and DNA damage response (DDR) activation in DNA damage sensing and signaling to maintain genome integrity. However, the cancer-associated mutations of TOPBP1 have not been well studied. Here, 369 variants of TOPBP1 across 31 types of human cancer from three databases: The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC) and Catalogue of Somatic Mutations in Cancer (COSMIC), were analyzed. We found that six truncation mutations of TOPBP1 impaired its ability to repair DNA lesions and activate damage checkpoint, and ten missense mutations impaired the recruitment of TOPBP1 to DNA damage sites. Therefore, DNA damage repair capacity and cell cycle arrest in G2/M phase were disrupted. The structural modeling also confirms that missense mutations of TOPBP1 change the local spatial structure, which may further abolish the function of TOPBP1 in DDR. Taken together, our study reveals the functional defects of cancer-associated TOPBP1 mutations in DDR and may provide new therapy targets for cancer treatment.
  PubDate: 2022-04-27
Correction to: p53 regulation by ubiquitin and ubiquitin-like
modifications
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  PubDate: 2022-04-06
DNA damage accumulation in aging brain and its links to Alzheimer’s
disease progression
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  Abstract: Abstract DNA, which carries information to build the entire human body, is constantly challenged by a variety of endogenous and environmental agents, ultimately leading to mutations and genomic instability, triggering a wide range of cellular responses and causing diverse human diseases. Cells have evolved a variety of DNA repair mechanisms to respond to DNA damage. Recent findings have linked DNA damage in the brain with many neurological diseases. In this review, we discuss how DNA damage in the brain correlates with Alzheimer’s disease and how the absence of repair mechanisms accelerates age-related Alzheimer’s disease progression. We also review the potential sources of DNA damage, which may be closely associated with cognitive decline in Alzheimer’s disease.
  PubDate: 2022-03-23
Target residence of Cas9: challenges and opportunities in genome editing
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  Abstract: Abstract CRISPR/Cas9 genome editing is a latest success in biotechnology that repurposes a natural biological system for a practical tool in genetic engineering. Site-specific DNA double strand breaks (DSB) induced by the CRISPR nuclease Cas9 allows endogenous cellular repair apparatus to generate desired repair products. Residence of Cas9 on cleaved DNA conceals the DNA ends from recognition by response and repair apparatus, delaying DNA damage response (DDR) and repair. Thus, tight-binding and long residence of Cas9 on DNA target are proposed as a new determinant of DSB repair pathway choice and may collaborate with other endogenous pathway choice regulators to control DSB repair. Accordingly, harnessing the binding and resident behavior of Cas9 not only broadens the application of CRISPR/dCas9 platform, which at least in part depends upon the tight binding and long residence of dCas9, but also minimizes the undesired outcomes of CRISPR/Cas9 genome editing.
  PubDate: 2022-03-23
Centrosome, microtubule and DNA damage response
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  Abstract: Abstract Centrosomes are the major microtubule-organizing center (MTOC), which are important cytoplasmic organelles regulating cell cycle, cell morphology, genomic stability, etc. The role of centrosomes on genomic stability has been reported in different conditions. Centrosomal proteins such as centrin2, pericentrin (PCNT), CEP164 have been reported to facilitate DNA damage repair. Various DNA damage response (DDR) proteins locate on centrosomes or microtubules, such as ATM, ATR, DNA-PKcs, 53BP1, etc. Meanwhile, microtubules serve as the “highway” for the transportation of DNA damage proteins into the nucleus. Microtubules have also been discovered to regulate the DNA double strands breaks (DSBs) mobility in DSBs repair. In this review, we first summarize the association between centrosome, microtubules, and DDR. Further, we discuss the new progression on how cells coordinate DDR with microtubule dynamics to facilitate DSBs repair.
  PubDate: 2022-03-22
Differential molecular alterations promoting non-small cell lung cancer
under hypoxia
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  Abstract: Abstract Hypoxia is one of the hallmarks of the solid cancer microenvironment that dominates cancer progression and exacerbation. Under the oxygen-deprived condition, cancer resists and circumvents all interventions for permanence. Genomic and genetic instability of hypoxic cancer remains to be insightfully investigated and interpreted, as in lung adenocarcinoma. Herein, non-small cell lung cancer (NSCLC) cell line A549 was exposed to hypoxic shots parallel with running non-hypoxic (normoxic) A549 cells. Based on the isolated total RNA, gene transcriptomic profiling was identified using microarray and analysed via Ingenuity Pathway Analysis (IPA). As well, wound healing and cytotoxicity of doxorubicin were performed to assess hypoxic lung cancer cell response. Gene expression analysis revealed that TP53 (p53) is the most activated signaling, along with suppression of chromosomal signalings (DNA replication and repair). Besides, TP53 and its dependent target CDKN1A/p21 (cell cycle down-regulator) were identified as the topmost significant upstream transcriptional regulators, commanding a 37-gene targetable panel for cancer survival. In addition, hypoxic A549 cells were more chemo-resistant and higher motile. Notably, other emerging alterations were detected regarding efflux transporters (ABC-As and ABC-G1) that have been selectively up-regulated over the rest of under-transcribed (ABC) transporters subfamilies. Together, these involved findings suggest that the p53 signaling could be a potential survival mediator of hypoxic NSCLC cells (A549), which triggered the prominent cell cycle down-regulation to frustrate apoptotic response in hypoxic NSCLC. Coupled with the impairing of DNA replication and repair signalings that promoted molecular alterations for survival. Represented by the remarkable epithelial-mesenchymal transition of hypo-proliferating hypoxic A549 cells by which was described at the transcriptional level alongside phenotypic level. Consequently, hypoxic A549 cells showed higher resistance to doxorubicin targeting DNA replication, regardless of any transcriptionally down-regulated (ABC) transporters.
  PubDate: 2022-03-21
Long non-coding RNAs regulate fatty acid and cholesterol metabolism
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  Abstract: Abstract In recent years, long non-coding RNAs (lncRNAs) have emerged as critical players in regulating biological processes at various levels. LncRNAs modulate the target genes through interacting with DNA, RNA, or protein, which have been found to regulate various physiological and pathological activities. Current studies have reported lncRNAs played an important role in lipid metabolism via diverse pathways. Dysregulation of lipid metabolism is closely related to various metabolic diseases, including obesity, fatty liver disease, and cancer. To further understand the mechanisms of lncRNAs in lipid metabolism, we focus on the role of lncRNAs in fatty acid and cholesterol biosynthesis, catabolism, and transferring, aiming to exploit relevant signaling pathways.
  PubDate: 2022-03-17
p53 regulation by ubiquitin and ubiquitin-like modifications
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  Abstract: Abstract The tumor suppressor p53 plays a central role in stress responses and tumor suppression. The increasingly complex p53 network is controlled by multiple layers of mechanisms, including the genetic level, transcriptional level, and protein level. Post-translational modifications (PTMs) of p53 represent a precise and efficient form of regulation. To date, the modification of p53 by ubiquitin and ubiquitin-like proteins (UBLs) has been studied extensively, including SUMOylation, NEDDylation, FATylation, ISGylation, and the recently identified UFMylation. They affect p53 stability, conformation, localization, transcriptional activity and binding partners. Here, we review these recent discoveries and summarize our understanding of ubiquitination and UBL modifications of p53 to better comprehend the complex landscape of p53 regulation. We will discuss how the ubiquitination and UBL modifications of p53 dynamically adjust its function to respond to various stress stimuli, thereby determining cell fate.
  PubDate: 2022-03-12
Single-stranded RNA viruses activate and hijack host apical DNA damage
response kinases for efficient viral replication
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  Abstract: Abstract The ataxia-telangiectasia mutated (ATM) and ATM-Rad3-related (ATR) are apical kinases that orchestrate the multifaceted DNA damage response (DDR) to a variety of genotoxic insults and regulate genomic stability. Whether RNA virus also manipulates the host’s DDR machine to facilitate replication is largely unknown. In this study, we revealed that single-stranded RNA virus replication specifically elicits host ATM- and ATR-mediated pathway activation and boosts their expression. The activated ATM and ATR are hijacked to the virus replication factory in the cytoplasm and facilitate viral gene expression and replication. Specific inhibitors targeting ATM and ATR strikingly block the viral proliferation and replication and inhibit expression of virus proteins. Our results reveal a novel, or otherwise noncanonical, conserved function of ATM/ATR outside DDR in promoting the replication of single-stranded RNA virus and provide an important mechanism of host–pathogen interactions.
  PubDate: 2022-02-28
  DOI: 10.1007/s42764-022-00064-3
MRE11-RAD50-NBS1-CtIP: one key nuclease ensemble functions in the
maintenance of genome stability
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  Abstract: Abstract To safeguard genome integrity, cells channel DNA double-strand breaks (DSBs) to repair pathway of either DNA end-joining or homology-directed repair. The MRE11-RAD50-NBS1 (MRN) complex functions in both pathways, teaming up with the right co-factors to ensure the correct repair of DSBs. The MRN complex is well known as a nuclease capable of resecting DNA in both endonucleolytic and exonucleolytic manners. At occupied DSB ends, DNA end resection is initiated by the “endonucleolytic cleavage followed by exonucleolytic digestion” action of MRN, with endonucleolytic cleavage specifically requiring phosphorylated CtIP being present. Previous studies by us and the other groups in the field help to uncover the mechanistic details of the MRN-CtIP nuclease ensemble functioning in DNA end resection and homologous recombination (HR), although many unclear parts still exist. Besides DSB repair, replication fork processing, R-loop, and transcription–replication conflict (TRC) resolution also have been suggested by accumulating studies to be relevant to MRN and CtIP. In this review, we will summarize current knowledge about the MRN-CtIP nuclease ensemble, its functions in DNA processing in various contexts that could generate genome instability, how this complex is regulated and its relevance to diseases like cancers.
  PubDate: 2022-02-23
  DOI: 10.1007/s42764-022-00065-2
Proteome profiling of phosphatidylinositol-5-phosphate 4-kinase type 2A
and 2B knockdown cells identify modifications in key regulators involved
in cell homeostasis and genome integrity
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  Abstract: Abstract Phosphatidylinositol-5-phosphate 4-kinases (PIP4K) are multiple cellular process regulatory lipid kinases. PIP4K2A and PIP4K2B are overexpressed in cancer. The recently reported kinase-independent role of PIP4K2A and PIP4K2B underscore the complexity of the underlying molecular changes and mechanisms involved. Here, we show proteome analysis of PIP4K2A, PIP4K2B and PIP4K2A/2B co-depleted osteosarcoma cells to reflect changes in protein expression and their post-translational modifications. PIP4K2A depletion mainly affects ribosome assembly, translation and cell proliferation. Proteins of the apoptotic process, DNA repair, and cell division are mainly affected in PIP4K2B knockdown cells. PIP4K2A/2B co-depletion affects proteins regulating vesicle transport, cell motility, RNA splicing, and cell division. PIP4K depletion also affects post-translational modifications (phosphorylation, acetylation) of proteins involved mainly in nucleosome organization, mRNA splicing, and DNA replication. In addition, we observed PIP4K2A and PIP4K2B overexpression in cells harbouring K-Ras G12V or G12D mutations. Collectively, our results show that single or co-depletion of the PIP4K isoforms regulate proteins participating in metabolism and maintenance of genome integrity. Given that PIP4K2A and PIP4K2B alter proteins related to genome instability and their role in cancer, these enzymes could be promising therapeutic targets for cells experiencing genotoxic stress conditions.
  PubDate: 2022-02-22
  DOI: 10.1007/s42764-022-00060-7
Biological function and regulation of histone 4 lysine 20 methylation in
DNA damage response
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  Abstract: Abstract Cells are often under attack from various DNA-damaging agents. Accurate repair is required to protect cells from the genome instability induced by DNA lesions. DNA damage response (DDR) signaling involves sensitizing, transmitting, and repairing different types of damage within chromatin complexes. Chromatin is a highly ordered complex packed with repeating units of nucleosomes and linker DNA sequences. Chromatin structure, gene transcription, and various biological processes are regulated by histone post-translational modifications (PTMs), including acetylation, methylation, phosphorylation, and ubiquitylation. Of these, the involvement of lysine methylation, regulated by numerous lysine methyltransferases and demethylases, in the DDR has been extensively explored. In particular, histone 4 lysine 20 methylation is one of the most essential histone PTMs for biological processes and ensures genome integrity. In this review, we summarize the dynamics and modulations of histone lysine methylation during the DDR. We also comprehensively describe the functions, mechanisms, and regulation of H4K20 methylation and its modifying enzymes in response to DNA damage.
  PubDate: 2022-02-07
  DOI: 10.1007/s42764-022-00063-4
Ubiquitin carboxyl-terminal hydrolase 11 promotes autophagy by
de-ubiquitinating and stabilizing Beclin-1
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  Abstract: Abstract Autophagy is a major degradation process that degrades and recycles cytoplasmic materials through lysosome for maintaining cellular homeostasis. Dysregulated autophagy is linked with numerous human diseases including cancer. Autophagy marker protein B-cell lymphoma-2 interacting protein 1 (Beclin-1) is essential for autophagosome initiation and maturation. Recently, Ubiquitin carboxyl-terminal hydrolase 11 (USP11) has been reported to promote or inhibit autophagy without identification of any direct target. Here through biochemical reaction in vitro, we demonstrate that USP11 directly interacts with Beclin-1. Both in vitro and in vivo de-ubiquitination assays revealed that USP11 de-ubiquitinates Beclin-1. USP11-mediated de-ubiquitination stabilized Beclin-1 and enhanced the formation of the autophagy-specific class III phosphatidylinositol 3-kinase complexes 1 and 2, thereby promoting autophagy. Together, our results demonstrated that USP11 promotes autophagy under unperturbed conditions by de-ubiquitinating and stabilizing Beclin-1 which may serve as a therapeutic target for autophagy-related diseases.
  PubDate: 2022-02-06
  DOI: 10.1007/s42764-022-00061-6
The role of ral signaling and post translational modifications (PTMs) of
Ras in cancer
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  Abstract: Abstract Mutation in RAS gene is one of the most common genetic alterations, which seems to be seen in one third of human cancers. Ras, as a molecular switch, has been considered in wide variety of signaling pathways such as cell division and apoptosis. Ras proteins have a binary function to transmit different extracellular messages into intracellular signaling network. It has been proved that Ras proteins associate with different plasma membranes. Although all Ras isoforms have been found at plasma membrane, H-Ras and N-Ras are located in Golgi, and K-Ras at ER and mitochondria outer membrane. There have been a lot of efforts to inhibit Ras signaling that can be a pivotal approach to treat Ras-induced tumors. Effect of RalA and RalB on the growth of embryonal tumors, at downstream region of Ras, has been studied in a number of studies, which showed that inhibition of these signaling pathways can provide a strong therapeutic approach to cancer. Also, post translational modifications (PTMs) in proteins interfere extremely with cell signaling pathways in cells that can react to external signals. In this review, the role of Ral signaling in cancer and PTM of Ras proteins has been reviewed.
  PubDate: 2022-01-17
  DOI: 10.1007/s42764-022-00059-0
Genotoxicity testing and recent advances
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  Abstract: Abstract Genotoxicity testing, a technique which is used to identify chemicals that cause genetic alterations, includes tests that aid determination of irreversible genetic alterations, as well as those that provide indirect evidence of DNA damage. A panel of tests is commonly considered to comprehensively evaluate the ability of a chemical to induce genotoxicity, since individual tests do not provide information on all end points. Although a standard panel for genotoxicity testing has been considered traditionally for decades, changes based on novel and emerging methodologies have been introduced. The present review provides a brief introduction to the commonly used basic tests intended for regulatory purposes, advanced genotoxicity testing including cells used in genotoxicity testing, application of quantitative structure activity relationship (QSAR), representative genotoxicity high-throughput in vitro assays, and high-dimensional/high information content assays, with specific reference to the application of next-generation sequencing (NGS), which enable genome-wide analyses of mutations in non-cancer cells, thereby revealing the effects of various environmental mutagens.
  PubDate: 2021-12-04
  DOI: 10.1007/s42764-021-00058-7
Correction to: Chromosome instability induced by mutations in TAD anchors
leads to tumors
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  PubDate: 2021-12-01
  DOI: 10.1007/s42764-021-00054-x
Nature of spontaneously arising single base substitutions in normal cells
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  Abstract: Abstract Next-generation sequencing (NGS) of single cells and micro-dissected tissues has demonstrated that the number of somatic mutations in normal cells increases linearly with age. The majority of somatic mutations are single base substitutions (SBSs). NGS has revealed the mutagenic effect of various metabolic and environmental genotoxic agents on different cells, such as normal colonic epithelial cells, hematopoietic cells, hepatocytes, and neurons. NGS has also uncovered the clonal expansion of cells in normal tissues of the elderly driven by oncogenic mutations. There are two main mechanisms for the generation of mutations, namely, replication errors and DNA damage, with both being followed by inaccurate repair. NGS studies of normal tissues highlight the substantial contribution of the latter mechanism by revealing the significant accumulation of somatic mutations in mitotically inactive hepatocytes and neurons. This review describes the nature of spontaneously arising SBSs in normal tissues, the causes of mutagenesis, cellular pathways of the DNA damage response that suppress mutagenesis, as well as unsolved questions on the matter.
  PubDate: 2021-12-01
  DOI: 10.1007/s42764-021-00056-9
Genome instability in pathogenesis of tuberculosis
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  Abstract: Abstract Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a serious global health problem that kills over 1 million people annually. Understanding the pathogenesis of TB and the emergence of drug-resistant strains of Mtb is a priority for the development of strategies against TB. Its DNA damage and repair systems are essential for maintaining genome stability in Mtb. Their aberrant work leads to hypermutability and is often associated with the emergence of resistant bacteria. On the other hand, Mtb infection also induces genome instability of host cells, which are involved in the pathogenesis of TB, including the formation of giant cells. Collectively, this review is an attempt to summarize our current understanding of the role of genome instability in the pathogenesis of TB and to shed light on the development of new strategies for TB treatment.
  PubDate: 2021-12-01
  DOI: 10.1007/s42764-021-00057-8
Chromosome instability induced by mutations in TAD anchors leads to tumors
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  Abstract: Abstract In the light of recent data, a way is described between mutations in TAD anchors and stimulation of tumor growth driven by chromosome instability. At the end of this way every tumor sacrifices by a portion of its cells, dying necrotically, to stimulate remaining cells to proliferate. Necrosis (cell puncture and leakage of chemokine CXCL12) launches the mechanism of wound healing that stimulates cells to divide. Necrosis in cancer cells is induced by chromosome aberrations hindering anaphase cleavage furrow ingression and leading to membrane rupture. Inherited chromosome instability arises, because some of DNA loops (gene blocks, also called TADs) are torn off chromatid axes at their attachment points (anchors) because of mutations at some of these points. Namely, CTCF target sites (CCXXXAGGGGG) at the basements of TAD loops acquire mutations in central Adenine and in 3–5 nucleotides just beyond the borders of this 11 bp sequence. The sequence itself is degenerate between different TADs mainly at the X nucleotides, rarely at some others. Interstitial satellite DNA (SAT) adjacent to TADs anchors begins to behave such as telomeric satellite DNA. This launches transcription of such erupted satellites not leaned against TADs and production of their DNA copies due to the action of TERT reverse transcriptase just like in telomeres and leads to insertion of telomere sequences into such SATs. Some sticky ends in satellites also add to chromosome instability.
  PubDate: 2021-09-29
  DOI: 10.1007/s42764-021-00050-1