P21 is a flexible, multi-functional protein. It governs various tumor cell activities, including autophagy. p21 is a possible radiotherapy target

Mapping Intimacies ◽

10.31219/osf.io/ydkca ◽

2021 ◽

Author(s):

Moataz Dowaidar

Keyword(s):

Cell Cycle ◽

Dna Repair ◽

Tumor Microenvironment ◽

Tumor Cell ◽

Radiation Exposure ◽

Future Study ◽

Regulatory Role ◽

Post Translational Modification ◽

Functional Protein ◽

Cellular Processes

p21 is a versatile protein with a lot of different functions. P21 controls several cellular processes in the tumor, including cell cycle, DNA repair, apoptosis, senescence, autophagy, and the tumor microenvironment, in response to radiation exposure. The fact that it is engaged in both of these processes makes things much more puzzling. As a result, truly grasping p21 continues to be a challenge. Researchers have begun to pay attention to p21 and consider it a potential radiotherapeutic target because of its robust regulatory role. The methods by which p21 performs contradictory tasks should be the focus of future study, as well as how to control its oncogenicity selectively. In biological systems, p21 can play a range of roles according to its many post-translational modification sites. The ability to strike a balance between p21's many functions might be the secret to successful radiotherapy.

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Evidence for a Structural Relationship between BRCT Domains and the Helicase Domains of the Replication Initiators Encoded by the Polyomaviridae and Papillomaviridae Families of DNA Tumor Viruses

Journal of Virology ◽

10.1128/jvi.00553-08 ◽

2008 ◽

Vol 82 (17) ◽

pp. 8849-8862 ◽

Cited By ~ 2

Author(s):

Anuradha Kumar ◽

Woo S. Joo ◽

Gretchen Meinke ◽

Stephanie Moine ◽

Elena N. Naumova ◽

...

Keyword(s):

Cell Cycle ◽

Dna Repair ◽

Cell Cycle Progression ◽

Cell Cycle Control ◽

Cellular Proteins ◽

Cycle Progression ◽

Cellular Processes ◽

Tumor Viruses ◽

Cellular Pathways ◽

Regulation Of Cell Cycle

ABSTRACT Studies of DNA tumor viruses have provided important insights into fundamental cellular processes and oncogenic transformation. They have revealed, for example, that upon expression of virally encoded proteins, cellular pathways involved in DNA repair and cell cycle control are disrupted. Herein, evidence is presented that BRCT-related regions are present in the helicase domains of the viral initiators encoded by the Polyomaviridae and Papillomaviridae viral families. Of interest, BRCT domains in cellular proteins recruit factors involved in diverse pathways, including DNA repair and the regulation of cell cycle progression. Therefore, the viral BRCT-related regions may compete with host BRCT domains for particular cellular ligands, a process that would help to explain the pleiotropic effects associated with infections with many DNA tumor viruses.

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Potential Roles of Tumor Cell- and Stroma Cell-Derived Small Extracellular Vesicles in Promoting a Pro-Angiogenic Tumor Microenvironment

Cancers ◽

10.3390/cancers12123599 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3599

Author(s):

Nils Ludwig ◽

Dominique S. Rubenich ◽

Łukasz Zaręba ◽

Jacek Siewiera ◽

Josquin Pieper ◽

...

Keyword(s):

Tumor Microenvironment ◽

Nucleic Acids ◽

Tumor Cell ◽

Extracellular Vesicles ◽

Potential Role ◽

Cell Types ◽

Signaling Cascades ◽

Functional Protein ◽

Surface Molecules ◽

Stroma Cell

Extracellular vesicles (EVs) are produced and released by all cells and are present in all body fluids. They exist in a variety of sizes, however, small extracellular vesicles (sEVs), the EV subset with a size range from 30 to 150 nm, are of current interest. They are characterized by a distinct biogenesis and complex cargo composition, which reflects the cytosolic contents and cell-surface molecules of the parent cells. This cargo consists of proteins, nucleic acids, and lipids and is competent in inducing signaling cascades in recipient cells after surface interactions or in initiating the generation of a functional protein by delivering nucleic acids. Based on these characteristics, sEVs are now considered as important mediators of intercellular communication. One hallmark of sEVs is the promotion of angiogenesis. It was shown that sEVs interact with endothelial cells (ECs) and promote an angiogenic phenotype, ultimately leading to increased vascularization of solid tumors and disease progression. It was also shown that sEVs reprogram cells in the tumor microenvironment (TME) and act in a functionally cooperative fashion to promote angiogenesis by a paracrine mechanism involving the differential expression and secretion of angiogenic factors from other cell types. In this review, we will focus on the distinct functions of tumor-cell-derived sEVs (TEX) in promotion of angiogenesis and describe their potential as a therapeutic target for anti-angiogenic therapies. Also, we will focus on non-cancer stroma-cell-derived small extracellular vesicles and their potential role in stimulating a pro-angiogenic TME.

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DNA Repair and Cell Cycle Biomarkers of Radiation Exposure and Inflammation Stress in Human Blood

PLoS ONE ◽

10.1371/journal.pone.0048619 ◽

2012 ◽

Vol 7 (11) ◽

pp. e48619 ◽

Cited By ~ 44

Author(s):

Helen Budworth ◽

Antoine M. Snijders ◽

Francesco Marchetti ◽

Brandon Mannion ◽

Sandhya Bhatnagar ◽

...

Keyword(s):

Cell Cycle ◽

Dna Repair ◽

Radiation Exposure ◽

Human Blood

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Multiple mechanisms account for genomic instability and molecular mutation in neoplastic transformation

Clinical Chemistry ◽

10.1093/clinchem/41.5.644 ◽

1995 ◽

Vol 41 (5) ◽

pp. 644-657 ◽

Cited By ~ 25

Author(s):

W B Coleman ◽

G J Tsongalis

Keyword(s):

Cell Cycle ◽

Dna Repair ◽

Dna Replication ◽

Genomic Instability ◽

Molecular Mechanisms ◽

Target Genes ◽

Neoplastic Transformation ◽

Molecular Alteration ◽

Cellular Processes ◽

Genes Encoding

Abstract Neoplastic cells typically possess numerous genomic mutations and chromosomal aberrations, including point mutations, gene amplifications and deletions, and replication errors. Acquisition of such genomic instability may represent an early step in the process of carcinogenesis. Proteins involved in DNA replication, DNA repair, cell cycle progression, and others are all components of complex overlapping biochemical pathways that function to maintain cellular homeostasis. Therefore, mutational alteration of genes encoding proteins involved in these cellular processes could contribute to genomic instability. Loss of normal cellular mechanisms that guard against genomic mutation and the ensuing genomic instability might lead to accumulation of multiple stable mutations in the genome of affected cells, perhaps resulting in neoplastic transformation when some critical number of transformation-related target genes become damaged. Thus, interactions of fundamental cellular processes play significant roles in sustaining cellular normality, and alteration of any of these homeostatic processes could entrain cells to the progressive genomic instability and phenotypic evolution characteristic of carcinogenesis. Here, we discuss possible molecular mechanisms governing DNA mutation and genomic instability in genetically normal cells that might account for the acquisition of genomic instability in somatic cells, leading to the development of neoplasia. These include (a) molecular alteration of genes encoding DNA repair enzymes, (b) molecular alteration of genes responsible for cell-cycle control mechanisms, and (c) direct molecular alteration of dominantly transforming cellular protooncogenes. We also discuss normal cellular processes involved with DNA replication and repair that can contribute to the mutational alteration of critical genes: e.g., slow repair of damaged DNA in specific genes, and the timing of normal gene-specific replication.

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Regulation of the cell cycle and centrosome biology by deubiquitylases

Biochemical Society Transactions ◽

10.1042/bst20170087 ◽

2017 ◽

Vol 45 (5) ◽

pp. 1125-1136 ◽

Cited By ~ 6

Author(s):

Sarah Darling ◽

Andrew B. Fielding ◽

Dorota Sabat-Pośpiech ◽

Ian A. Prior ◽

Judy M. Coulson

Keyword(s):

Cell Cycle ◽

Cell Division ◽

Mitotic Spindle ◽

Mammalian Cells ◽

Genetic Material ◽

Post Translational Modification ◽

Cellular Processes ◽

Daughter Cells ◽

Damage Response ◽

A Cell

Post-translational modification of proteins by ubiquitylation is increasingly recognised as a highly complex code that contributes to the regulation of diverse cellular processes. In humans, a family of almost 100 deubiquitylase enzymes (DUBs) are assigned to six subfamilies and many of these DUBs can remove ubiquitin from proteins to reverse signals. Roles for individual DUBs have been delineated within specific cellular processes, including many that are dysregulated in diseases, particularly cancer. As potentially druggable enzymes, disease-associated DUBs are of increasing interest as pharmaceutical targets. The biology, structure and regulation of DUBs have been extensively reviewed elsewhere, so here we focus specifically on roles of DUBs in regulating cell cycle processes in mammalian cells. Over a quarter of all DUBs, representing four different families, have been shown to play roles either in the unidirectional progression of the cell cycle through specific checkpoints, or in the DNA damage response and repair pathways. We catalogue these roles and discuss specific examples. Centrosomes are the major microtubule nucleating centres within a cell and play a key role in forming the bipolar mitotic spindle required to accurately divide genetic material between daughter cells during cell division. To enable this mitotic role, centrosomes undergo a complex replication cycle that is intimately linked to the cell division cycle. Here, we also catalogue and discuss DUBs that have been linked to centrosome replication or function, including centrosome clustering, a mitotic survival strategy unique to cancer cells with supernumerary centrosomes.

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Targeting DNA Repair, Cell Cycle, and Tumor Microenvironment in B Cell Lymphoma

Cells ◽

10.3390/cells9102287 ◽

2020 ◽

Vol 9 (10) ◽

pp. 2287

Author(s):

Paul J. Bröckelmann ◽

Mathilde R. W. de Jong ◽

Ron D. Jachimowicz

Keyword(s):

Cell Cycle ◽

Dna Repair ◽

Tumor Microenvironment ◽

B Cell ◽

Genome Stability ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Cell Development ◽

B Cell Development ◽

Cell Cycle Checkpoints

The DNA double-strand break (DSB) is the most cytotoxic lesion and compromises genome stability. In an attempt to efficiently repair DSBs, cells activate ATM kinase, which orchestrates the DNA damage response (DDR) by activating cell cycle checkpoints and initiating DSB repair pathways. In physiological B cell development, however, programmed DSBs are generated as intermediates for effective immune responses and the maintenance of genomic integrity. Disturbances of these pathways are at the heart of B cell lymphomagenesis. Here, we review the role of DNA repair and cell cycle control on B cell development and lymphomagenesis. In addition, we highlight the intricate relationship between the DDR and the tumor microenvironment (TME). Lastly, we provide a clinical perspective by highlighting treatment possibilities of defective DDR signaling and the TME in mantle cell lymphoma, which serves as a blueprint for B cell lymphomas.

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Poly(ADP-ribosyl)ation reactions in the regulation of nuclear functions

Biochemical Journal ◽

10.1042/bj3420249 ◽

1999 ◽

Vol 342 (2) ◽

pp. 249-268 ◽

Cited By ~ 518

Author(s):

Damien d'AMOURS ◽

Serge DESNOYERS ◽

Icy d'SILVA ◽

Guy G. POIRIER

Keyword(s):

Dna Repair ◽

Protein Interactions ◽

Physiological Role ◽

Polymer Chains ◽

Protein Protein Interactions ◽

Post Translational Modification ◽

Strand Breaks ◽

Cellular Processes ◽

Dna Strand

Poly(ADP-ribosyl)ation is a post-translational modification of proteins. During this process, molecules of ADP-ribose are added successively on to acceptor proteins to form branched polymers. This modification is transient but very extensive in vivo, as polymer chains can reach more than 200 units on protein acceptors. The existence of the poly(ADP-ribose) polymer was first reported nearly 40 years ago. Since then, the importance of poly(ADP-ribose) synthesis has been established in many cellular processes. However, a clear and unified picture of the physiological role of poly(ADP-ribosyl)ation still remains to be established. The total dependence of poly(ADP-ribose) synthesis on DNA strand breaks strongly suggests that this post-translational modification is involved in the metabolism of nucleic acids. This view is also supported by the identification of direct protein-protein interactions involving poly(ADP-ribose) polymerase (113 kDa PARP), an enzyme catalysing the formation of poly(ADP-ribose), and key effectors of DNA repair, replication and transcription reactions. The presence of PARP in these multiprotein complexes, in addition to the actual poly(ADP-ribosyl)ation of some components of these complexes, clearly supports an important role for poly(ADP-ribosyl)ation reactions in DNA transactions. Accordingly, inhibition of poly(ADP-ribose) synthesis by any of several approaches and the analysis of PARP-deficient cells has revealed that the absence of poly(ADP-ribosyl)ation strongly affects DNA metabolism, most notably DNA repair. The recent identification of new poly(ADP-ribosyl)ating enzymes with distinct (non-standard) structures in eukaryotes and archaea has revealed a novel level of complexity in the regulation of poly(ADP-ribose) metabolism.

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XAB2 Dynamics during DNA Damage-Dependent Transcription Inhibition

10.1101/2021.12.23.473962 ◽

2021 ◽

Author(s):

Lise-Marie DONNIO ◽

Elena Cerutti ◽

Charlene Magnani ◽

Damien Neuillet ◽

Pierre-Olivier Mari ◽

...

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Excision Repair ◽

Uv Light ◽

Critical Role ◽

Functional Protein ◽

Cellular Processes ◽

Damage Recognition ◽

Fast Change ◽

Group A

Xeroderma Pigmentosum group A (XPA)-binding protein 2 (XAB2) is a multi-functional protein that plays a critical role in distinct cellular processes including transcription, splicing, DNA repair and mRNA export. In this study, we detailed XAB2 involvement during Nucleotide Excision Repair (NER), a repair pathway that guarantees genome integrity against UV light-induced DNA damage and that specifically removes transcription-blocking damage in a dedicated process known as Transcription-Coupled repair (TC-NER). Here, we demonstrated that XAB2 is involved specifically and exclusively in TC-NER reaction and solely for RNA Polymerase 2 transcribed genes. Surprisingly, contrary to all the other NER proteins studied so far, XAB2 does not accumulate on the local UV-C damage but on the contrary is remobilized after damage induction. This fast change in mobility is restored when DNA repair reactions are completed. By scrutinizing from which cellular complex/partner/structure XAB2 is released, we have identified that XAB2 is detached after DNA damage induction from the DNA:RNA hybrids, commonly known as R-loops, and the CSA and XPG protein and this release is thought to contribute to the DNA damage recognition step during TC-NER. Importantly, we have disclosed a role for XAB2 in retaining RNAP2 on its substrate.

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