scholarly journals Vimentin protects cells against nuclear rupture and DNA damage during migration

2019 ◽  
Vol 218 (12) ◽  
pp. 4079-4092 ◽  
Author(s):  
Alison E. Patteson ◽  
Amir Vahabikashi ◽  
Katarzyna Pogoda ◽  
Stephen A. Adam ◽  
Kalpana Mandal ◽  
...  
Keyword(s):  
Dna Damage ◽  
Mammalian Cells ◽  
Nuclear Shape ◽  
Null Mouse ◽  
Intermediate Filament Protein ◽  
Cell Periphery ◽  
Damage Repair ◽  
Repair Mechanisms ◽  
Filament Protein ◽  
Nuclear Rupture

Mammalian cells frequently migrate through tight spaces during normal embryogenesis, wound healing, diapedesis, or in pathological situations such as metastasis. Nuclear size and shape are important factors in regulating the mechanical properties of cells during their migration through such tight spaces. At the onset of migratory behavior, cells often initiate the expression of vimentin, an intermediate filament protein that polymerizes into networks extending from a juxtanuclear cage to the cell periphery. However, the role of vimentin intermediate filaments (VIFs) in regulating nuclear shape and mechanics remains unknown. Here, we use wild-type and vimentin-null mouse embryonic fibroblasts to show that VIFs regulate nuclear shape and perinuclear stiffness, cell motility in 3D, and the ability of cells to resist large deformations. These changes increase nuclear rupture and activation of DNA damage repair mechanisms, which are rescued by exogenous reexpression of vimentin. Our findings show that VIFs provide mechanical support to protect the nucleus and genome during migration.

scholarly journals Vimentin protects the structural integrity of the nucleus and suppresses nuclear damage caused by large deformations

2019 ◽  
Author(s):  
Alison E Patteson ◽  
Amir Vahabikashi ◽  
Katarzyna Pogoda ◽  
Stephen A Adam ◽  
Anne Goldman ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Structural Integrity ◽  
Large Deformations ◽  
Nuclear Shape ◽  
Null Mouse ◽  
Intermediate Filament Protein ◽  
Cell Periphery ◽  
Damage Repair ◽  
Repair Mechanisms ◽  
3D Cell Migration

Mammalian cells frequently migrate through tight spaces during normal embryogenesis, wound healing, diapedesis or in pathological situations such as metastasis. The nucleus has recently emerged as an important factor in regulating 3D cell migration. At the onset of migratory behavior, cells often initiate the expression of vimentin, an intermediate filament protein which forms networks extending from a juxtanuclear cage to the cell periphery. However, the role of vimentin intermediate filaments (VIFs) in regulating nuclear shape and mechanics remains unknown. Here, we used wild type and vimentin-null mouse embryonic fibroblasts to show that VIFs regulate nuclear shape, motility, and the ability of cells to resist large deformations. The results show that loss of VIFs alters nuclear shape, reduces perinuclear stiffness, and enhances motility in 3D. These changes increase nuclear rupture and activation of DNA damage repair mechanisms, which are rescued by exogenous re-expression of vimentin. Our findings show that VIFs provide mechanical support to protect the nucleus and genome during migration.

scholarly journals Dephosphorylation of the C-terminal Tyrosyl Residue of the DNA Damage-related Histone H2A.X Is Mediated by the Protein Phosphatase Eyes Absent

2009 ◽  
Vol 284 (24) ◽  
pp. 16066-16070 ◽  
Author(s):  
Navasona Krishnan ◽  
Dae Gwin Jeong ◽  
Suk-Kyeong Jung ◽  
Seong Eon Ryu ◽  
Andrew Xiao ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Mammalian Cells ◽  
Protein Tyrosine Phosphatases ◽  
Histone H2a ◽  
Eyes Absent ◽  
Damage Repair ◽  
Damage Response

In mammalian cells, the DNA damage-related histone H2A variant H2A.X is characterized by a C-terminal tyrosyl residue, Tyr-142, which is phosphorylated by an atypical kinase, WSTF. The phosphorylation status of Tyr-142 in H2A.X has been shown to be an important regulator of the DNA damage response by controlling the formation of γH2A.X foci, which are platforms for recruiting molecules involved in DNA damage repair and signaling. In this work, we present evidence to support the identification of the Eyes Absent (EYA) phosphatases, protein-tyrosine phosphatases of the haloacid dehalogenase superfamily, as being responsible for dephosphorylating the C-terminal tyrosyl residue of histone H2A.X. We demonstrate that EYA2 and EYA3 displayed specificity for Tyr-142 of H2A.X in assays in vitro. Suppression of eya3 by RNA interference resulted in elevated basal phosphorylation and inhibited DNA damage-induced dephosphorylation of Tyr-142 of H2A.X in vivo. This study provides the first indication of a physiological substrate for the EYA phosphatases and suggests a novel role for these enzymes in regulation of the DNA damage response.

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 Ribosome profiling reveals a functional role for autophagy in mRNA translational control

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Juliet Goldsmith ◽  
Timothy Marsh ◽  
Saurabh Asthana ◽  
Andrew M. Leidal ◽  
Deepthisri Suresh ◽  
...  
Keyword(s):  
Dna Damage ◽  
Protein Synthesis ◽  
Translational Control ◽  
Mammalian Cells ◽  
Dna Damage Repair ◽  
Protein Translation ◽  
Ribosome Profiling ◽  
Parp Inhibition ◽  
Genetic Ablation ◽  
Damage Repair

AbstractAutophagy promotes protein degradation, and therefore has been proposed to maintain amino acid pools to sustain protein synthesis during metabolic stress. To date, how autophagy influences the protein synthesis landscape in mammalian cells remains unclear. Here, we utilize ribosome profiling to delineate the effects of genetic ablation of the autophagy regulator, ATG12, on translational control. In mammalian cells, genetic loss of autophagy does not impact global rates of cap dependent translation, even under starvation conditions. Instead, autophagy supports the translation of a subset of mRNAs enriched for cell cycle control and DNA damage repair. In particular, we demonstrate that autophagy enables the translation of the DNA damage repair protein BRCA2, which is functionally required to attenuate DNA damage and promote cell survival in response to PARP inhibition. Overall, our findings illuminate that autophagy impacts protein translation and shapes the protein landscape.

Dealing with transcription-blocking DNA damage: repair mechanisms, RNA polymerase II processing and human disorders

DNA Repair ◽  
2021 ◽  
pp. 103192
Author(s):  
Nan Jia ◽  
Chaowan Guo ◽  
Yuka Nakazawa ◽  
Diana van den Heuvel ◽  
Martijn S. Luijsterburg ◽  
...  
Keyword(s):  
Dna Damage ◽  
Rna Polymerase ◽  
Rna Polymerase Ii ◽  
Dna Damage Repair ◽  
Damage Repair ◽  
Repair Mechanisms ◽  
Human Disorders

scholarly journals DNA Damage/Repair Management in Cancers

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 1050 ◽  
Author(s):  
Jehad F. Alhmoud ◽  
John F. Woolley ◽  
Ala-Eddin Al Moustafa ◽  
Mohammed Imad Malki
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Dna Damage Repair ◽  
Critical Factor ◽  
Dna Lesions ◽  
Cancer Development ◽  
Dna Damaging Agents ◽  
Damage Repair ◽  
Repair Mechanisms ◽  
Dna Strand

DNA damage is well recognized as a critical factor in cancer development and progression. DNA lesions create an abnormal nucleotide or nucleotide fragment, causing a break in one or both chains of the DNA strand. When DNA damage occurs, the possibility of generated mutations increases. Genomic instability is one of the most important factors that lead to cancer development. DNA repair pathways perform the essential role of correcting the DNA lesions that occur from DNA damaging agents or carcinogens, thus maintaining genomic stability. Inefficient DNA repair is a critical driving force behind cancer establishment, progression and evolution. A thorough understanding of DNA repair mechanisms in cancer will allow for better therapeutic intervention. In this review we will discuss the relationship between DNA damage/repair mechanisms and cancer, and how we can target these pathways.

scholarly journals Oxidative DNA damage repair in mammalian cells: A new perspective

DNA Repair ◽  
2007 ◽  
Vol 6 (4) ◽  
pp. 470-480 ◽  
Author(s):  
T HAZRA ◽  
A DAS ◽  
S DAS ◽  
S CHOUDHURY ◽  
Y KOW ◽  
...  
Keyword(s):  
Dna Damage ◽  
Mammalian Cells ◽  
Oxidative Dna Damage ◽  
Dna Damage Repair ◽  
Damage Repair ◽  
New Perspective

scholarly journals DNA repair system defects - role in oncogenesis and cancer therapy

2014 ◽  
Vol 95 (3) ◽  
pp. 307-314
Author(s):  
S V Boychuk ◽  
B R Ramazanov
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Cancer Therapy ◽  
Single Case ◽  
Published Data ◽  
Repair System ◽  
Damage Repair ◽  
Anti Cancer ◽  
Repair Mechanisms ◽  
Acquired Abnormalities

Inherited and acquired abnormalities in DNA damage repair system may lead to cancer and other diseases, as well as to act as one of the key factors determining the patient’s responsiveness to chemo- and radiotherapy. Nowadays, the principles of the personalized therapy, based on specific features of disease development and pathogenesis of a solitary organism or in a small group, are applied to treat a broad number of diseases, including cancers. This approach allows to choose the most effective cancer therapy in every single case of cancer, based on the genetic analysis and expression level of specific proteins. One of the promising approaches for increasing the effectiveness of non-surgical cancer treatments - to develop the methods to increase the cancer cells sensitivity to conducted chemotherapy, based on using the DNA repair system defects for the better anti-cancer effect. The review covers some types of DNA repair system defects occurring while chemo- and radiotherapy. Perspectives of the possible influences on DNA repair mechanisms treated as possible targets for both anti-cancer treatment and for increasing the effects of cancer chemo- and radiotherapy, are discussed in the review considering the available published data and results of own research. DNA repair system defects play an important role in cancer genesis, but as well can determine the good response of patients with such defects to chemo- and radiotherapy (inducing different types of DNA damage).

scholarly journals Regulation of Genome Stability by TEL1 and MEC1, Yeast Homologs of the Mammalian ATM and ATR Genes

Genetics ◽  
2002 ◽  
Vol 161 (2) ◽  
pp. 493-507
Author(s):  
Rolf J Craven ◽  
Patricia W Greenwell ◽  
Margaret Dominska ◽  
Thomas D Petes
Keyword(s):  
Dna Damage ◽  
Telomere Length ◽  
Mammalian Cells ◽  
Genome Stability ◽  
Chromosome Loss ◽  
Yeast Saccharomyces Cerevisiae ◽  
Mutant Genotype ◽  
Dna Damaging Agents ◽  
Damage Repair ◽  
Length Regulation

Abstract In eukaryotes, a family of related protein kinases (the ATM family) is involved in regulating cellular responses to DNA damage and telomere length. In the yeast Saccharomyces cerevisiae, two members of this family, TEL1 and MEC1, have functionally redundant roles in both DNA damage repair and telomere length regulation. Strains with mutations in both genes are very sensitive to DNA damaging agents, have very short telomeres, and undergo cellular senescence. We find that strains with the double mutant genotype also have ∼80-fold increased rates of mitotic recombination and chromosome loss. In addition, the tel1 mec1 strains have high rates of telomeric fusions, resulting in translocations, dicentrics, and circular chromosomes. Similar chromosome rearrangements have been detected in mammalian cells with mutations in ATM (related to TEL1) and ATR (related to MEC1) and in mammalian cells that approach cell crisis.

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