scholarly journals Intracellular and Intercellular Signalling Mechanisms following DNA Damage Are Modulated By PINK1

2018 ◽  
Vol 2018 ◽  
pp. 1-15 ◽  
Author(s):  
Mihaela Temelie ◽  
Diana Iulia Savu ◽  
Nicoleta Moisoi
Keyword(s):  
Dna Damage ◽  
Mitochondrial Dysfunction ◽  
Cellular Response ◽  
Genotoxic Stress ◽  
Cell System ◽  
Dna Lesions ◽  
Loss Of Function ◽  
Adaptive Responses ◽  
Age Related ◽  
Intercellular Signalling

Impaired mitochondrial function and accumulation of DNA damage have been recognized as hallmarks of age-related diseases. Mitochondrial dysfunction initiates protective signalling mechanisms coordinated at nuclear level particularly by modulating transcription of stress signalling factors. In turn, cellular response to DNA lesions comprises a series of interconnected complex protective pathways, which require the energetic and metabolic support of the mitochondria. These are involved in intracellular as well as in extracellular signalling of damage. Here, we have initiated a study that addresses how mitochondria-nucleus communication may occur in conditions of combined mitochondrial dysfunction and genotoxic stress and what are the consequences of this interaction on the cell system. In this work, we used cells deficient for PINK1, a mitochondrial kinase involved in mitochondrial quality control whose loss of function leads to the accumulation of dysfunctional mitochondria, challenged with inducers of DNA damage, namely, ionizing radiation and the radiomimetic bleomycin. Combined stress at the level of mitochondria and the nucleus impairs both mitochondrial and nuclear functions. Our findings revealed exacerbated sensibility to genotoxic stress in PINK1-deficient cells. The same cells showed an impaired induction of bystander phenomena following stress insults. However, these cells responded adaptively when a challenge dose was applied subsequently to a low-dose treatment to the cells. The data demonstrates that PINK1 modulates intracellular and intercellular signalling pathways, particularly adaptive responses and transmission of bystander signalling, two facets of the cell-protective mechanisms against detrimental agents.

scholarly journals MORC2 regulates DNA damage response through a PARP1-dependent pathway

2019 ◽  
Vol 47 (16) ◽  
pp. 8502-8520 ◽  
Author(s):  
Lin Zhang ◽  
Da-Qiang Li
Keyword(s):  
Dna Damage ◽  
Zinc Finger ◽  
Chromatin Remodeling ◽  
Dna Damage Response ◽  
Mammalian Cells ◽  
Cellular Response ◽  
Genotoxic Stress ◽  
Underlying Mechanism ◽  
Dna Lesions ◽  
Damage Response

Abstract Microrchidia family CW-type zinc finger 2 (MORC2) is a newly identified chromatin remodeling enzyme with an emerging role in DNA damage response (DDR), but the underlying mechanism remains largely unknown. Here, we show that poly(ADP-ribose) polymerase 1 (PARP1), a key chromatin-associated enzyme responsible for the synthesis of poly(ADP-ribose) (PAR) polymers in mammalian cells, interacts with and PARylates MORC2 at two residues within its conserved CW-type zinc finger domain. Following DNA damage, PARP1 recruits MORC2 to DNA damage sites and catalyzes MORC2 PARylation, which stimulates its ATPase and chromatin remodeling activities. Mutation of PARylation residues in MORC2 results in reduced cell survival after DNA damage. MORC2, in turn, stabilizes PARP1 through enhancing acetyltransferase NAT10-mediated acetylation of PARP1 at lysine 949, which blocks its ubiquitination at the same residue and subsequent degradation by E3 ubiquitin ligase CHFR. Consequently, depletion of MORC2 or expression of an acetylation-defective PARP1 mutant impairs DNA damage-induced PAR production and PAR-dependent recruitment of DNA repair proteins to DNA lesions, leading to enhanced sensitivity to genotoxic stress. Collectively, these findings uncover a previously unrecognized mechanistic link between MORC2 and PARP1 in the regulation of cellular response to DNA damage.

Nuclear Genomic Instability and Aging

2018 ◽  
Vol 87 (1) ◽  
pp. 295-322 ◽  
Author(s):  
Laura J. Niedernhofer ◽  
Aditi U. Gurkar ◽  
Yinsheng Wang ◽  
Jan Vijg ◽  
Jan H.J. Hoeijmakers ◽  
...  
Keyword(s):  
Dna Damage ◽  
Genomic Instability ◽  
Nuclear Dna ◽  
Nuclear Genome ◽  
Accelerated Aging ◽  
Genotoxic Stress ◽  
Dna Lesions ◽  
Age Related ◽  
Damage Accrual ◽  
Theory Of Aging

The nuclear genome decays as organisms age. Numerous studies demonstrate that the burden of several classes of DNA lesions is greater in older mammals than in young mammals. More challenging is proving this is a cause rather than a consequence of aging. The DNA damage theory of aging, which argues that genomic instability plays a causal role in aging, has recently gained momentum. Support for this theory stems partly from progeroid syndromes in which inherited defects in DNA repair increase the burden of DNA damage leading to accelerated aging of one or more organs. Additionally, growing evidence shows that DNA damage accrual triggers cellular senescence and metabolic changes that promote a decline in tissue function and increased susceptibility to age-related diseases. Here, we examine multiple lines of evidence correlating nuclear DNA damage with aging. We then consider how, mechanistically, nuclear genotoxic stress could promote aging. We conclude that the evidence, in toto, supports a role for DNA damage as a nidus of aging.

scholarly journals Genomic and functional integrity of the hematopoietic system requires tolerance of oxidative DNA lesions

Blood ◽  
2017 ◽  
Vol 130 (13) ◽  
pp. 1523-1534 ◽  
Author(s):  
Ana Martín-Pardillos ◽  
Anastasia Tsaalbi-Shtylik ◽  
Si Chen ◽  
Seka Lazare ◽  
Ronald P. van Os ◽  
...  
Keyword(s):  
Dna Damage ◽  
Mitochondrial Dysfunction ◽  
Replication Stress ◽  
Precursor Cells ◽  
Dna Lesions ◽  
Hematopoietic Stem ◽  
Hematopoietic System ◽  
Functional Integrity ◽  
Key Points

Key Points Tolerance of oxidative DNA lesions ensures the genomic and functional integrity of hematopoietic stem and precursor cells. Endogenous DNA damage–induced replication stress is associated with mitochondrial dysfunction.

scholarly journals Cell Cycle and DNA Repair Regulation in the Damage Response: Protein Phosphatases Take Over the Reins

2020 ◽  
Vol 21 (2) ◽  
pp. 446 ◽  
Author(s):  
Adrián Campos ◽  
Andrés Clemente-Blanco
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cellular Response ◽  
Molecular Mechanisms ◽  
Protein Phosphatases ◽  
Genetic Material ◽  
Protein Composition ◽  
Genotoxic Stress ◽  
Damage Response ◽  
Protein Dephosphorylation

Cells are constantly suffering genotoxic stresses that affect the integrity of our genetic material. Genotoxic insults must be repaired to avoid the loss or inappropriate transmission of the genetic information, a situation that could lead to the appearance of developmental abnormalities and tumorigenesis. To combat this threat, eukaryotic cells have evolved a set of sophisticated molecular mechanisms that are collectively known as the DNA damage response (DDR). This surveillance system controls several aspects of the cellular response, including the detection of lesions, a temporary cell cycle arrest, and the repair of the broken DNA. While the regulation of the DDR by numerous kinases has been well documented over the last decade, the complex roles of protein dephosphorylation have only recently begun to be investigated. Here, we review recent progress in the characterization of DDR-related protein phosphatases during the response to a DNA lesion, focusing mainly on their ability to modulate the DNA damage checkpoint and the repair of the damaged DNA. We also discuss their protein composition and structure, target specificity, and biochemical regulation along the different stages encompassed in the DDR. The compilation of this information will allow us to better comprehend the physiological significance of protein dephosphorylation in the maintenance of genome integrity and cell viability in response to genotoxic stress.

scholarly journals DNA Damage-Inducing Anticancer Therapies: From Global to Precision Damage

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2098 ◽  
Author(s):  
Thom G. A. Reuvers ◽  
Roland Kanaar ◽  
Julie Nonnekens
Keyword(s):  
Dna Damage ◽  
Cellular Response ◽  
Cellular Proliferation ◽  
Dna Damage Repair ◽  
Therapy Response ◽  
Dna Lesions ◽  
Response To Therapy ◽  
Novel Therapy ◽  
Damage Repair ◽  
And Function

DNA damage-inducing therapies are of tremendous value for cancer treatment and function by the direct or indirect formation of DNA lesions and subsequent inhibition of cellular proliferation. Of central importance in the cellular response to therapy-induced DNA damage is the DNA damage response (DDR), a protein network guiding both DNA damage repair and the induction of cancer-eradicating mechanisms such as apoptosis. A detailed understanding of DNA damage induction and the DDR has greatly improved our knowledge of the classical DNA damage-inducing therapies, radiotherapy and cytotoxic chemotherapy, and has paved the way for rational improvement of these treatments. Moreover, compounds targeting specific DDR proteins, selectively impairing DNA damage repair in cancer cells, form a promising novel therapy class that is now entering the clinic. In this review, we give an overview of the current state and ongoing developments, and discuss potential avenues for improvement for DNA damage-inducing therapies, with a central focus on the role of the DDR in therapy response, toxicity and resistance. Furthermore, we describe the relevance of using combination regimens containing DNA damage-inducing therapies and how they can be utilized to potentiate other anticancer strategies such as immunotherapy.

scholarly journals Promyelocytic leukemia nuclear bodies behave as DNA damage sensors whose response to DNA double-strand breaks is regulated by NBS1 and the kinases ATM, Chk2, and ATR

2006 ◽  
Vol 175 (1) ◽  
pp. 55-66 ◽  
Author(s):  
Graham Dellaire ◽  
Reagan W. Ching ◽  
Kashif Ahmed ◽  
Farid Jalali ◽  
Kenneth C.K. Tse ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cellular Response ◽  
Cell Cycle Progression ◽  
Nuclear Body ◽  
Promyelocytic Leukemia ◽  
S Phase ◽  
Nuclear Bodies ◽  
Structural Basis ◽  
Loss Of Function

The promyelocytic leukemia (PML) nuclear body (NB) is a dynamic subnuclear compartment that is implicated in tumor suppression, as well as in the transcription, replication, and repair of DNA. PML NB number can change during the cell cycle, increasing in S phase and in response to cellular stress, including DNA damage. Although topological changes in chromatin after DNA damage may affect the integrity of PML NBs, the molecular or structural basis for an increase in PML NB number has not been elucidated. We demonstrate that after DNA double-strand break induction, the increase in PML NB number is based on a biophysical process, as well as ongoing cell cycle progression and DNA repair. PML NBs increase in number by a supramolecular fission mechanism similar to that observed in S-phase cells, and which is delayed or inhibited by the loss of function of NBS1, ATM, Chk2, and ATR kinase. Therefore, an increase in PML NB number is an intrinsic element of the cellular response to DNA damage.

scholarly journals Transcriptional profiling of the age-related response to genotoxic stress points to differential DNA damage response with age

2009 ◽  
Vol 130 (9) ◽  
pp. 637-647 ◽  
Author(s):  
Kirk Simon ◽  
Anju Mukundan ◽  
Samantha Dewundara ◽  
Holly Van Remmen ◽  
Alan A. Dombkowski ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Transcriptional Profiling ◽  
Genotoxic Stress ◽  
Age Related ◽  
Damage Response ◽  
Related Response

scholarly journals Pleiotropic actions of estrogen: a mitochondrial matter

2013 ◽  
Vol 45 (3) ◽  
pp. 106-109 ◽  
Author(s):  
Michael C. Velarde
Keyword(s):  
Mitochondrial Dysfunction ◽  
Cellular Response ◽  
Estrogen Replacement Therapy ◽  
Potential Role ◽  
Estrogen Replacement ◽  
Beneficial Effects ◽  
Age Related ◽  
Pleiotropic Action ◽  
Pleiotropic Actions

Estrogen provides many beneficial effects early in life by regulating normal tissue development and several physiological functions. While estrogen replacement therapy (ERT) in women was expected to reduce the health risks associated with the age-related decline in estrogen levels during menopause, ERT also resulted in increased progression to other types of diseases. Hence, distinguishing the signaling pathways that regulate the beneficial and detrimental effects of estrogen is important for developing interventions that selectively harness the hormone's beneficial effects, while minimizing its side effects. Estrogen can minimize mitochondrial dysfunction, which is thought to contribute to aging phenotypes. Decline in estrogen levels during menopause may lead to progressive mitochondrial dysfunction and may permanently alter cellular response, including that of estrogen (i.e., ERT). This review discusses the interplay between estrogen and mitochondrial function during the aging process and suggests a potential role of mitochondria in influencing the pleiotropic action of estrogen.

scholarly journals MicroRNA regulation of the MRN complex impacts DNA damage, cellular senescence and angiogenic signaling

2017 ◽  
Author(s):  
Cristina Espinosa-Diez ◽  
RaeAnna Wilson ◽  
Namita Chatterjee ◽  
Clayton Hudson ◽  
Rebecca Ruhl ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Targeted Delivery ◽  
Genotoxic Stress ◽  
Telomerase Activity ◽  
Loss Of Function ◽  
Mrn Complex ◽  
Vegf Signaling

AbstractMicroRNAs contribute to biological robustness by buffering cellular processes from external perturbations. Here we report an unexpected link between DNA damage response and angiogenic signaling that is buffered by two distinct microRNAs. We demonstrate that genotoxic stress-induced miR-494 and miR-99b inhibit the DNA repair machinery by targeting the MRE11a-RAD50-NBN (MRN) complex. Functionally, gain and loss of function experiments show that miR-494 and miR-99b affect telomerase activity, activate p21 and Rb pathways and diminish angiogenic sproutingin vitroandin vivo. Genetic and pharmacological disruption of VEGFR-2 signaling and the MRN complex reveal a surprising co-dependency of these pathways in regulating endothelial senescence and proliferation. Vascular-targeted delivery of miR-494 decreases both growth factor-induced and tumor angiogenesis in mouse models. Mechanistically, disruption of the MRN complex induced CD44, a known driver of senescence and regulator of VEGF signaling in addition to suppressing IL-13 a stimulator of VEGF signaling. Our work identifies a putative miR-facilitated mechanism by which endothelial cells can be insulated against VEGF signaling to facilitate the onset of senescence and highlight the potential of targeting DNA repair to disrupt pathological angiogenesis.

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