scholarly journals PARP mediated DNA damage response, genomic stability and immune responses

2021 ◽  
Author(s):  
Chunyan Zong ◽  
Tianyu Zhu ◽  
Jie He ◽  
Rui Huang ◽  
Renbing Jia ◽  
...  
Keyword(s):  
Dna Damage ◽  
Immune Responses ◽  
Dna Damage Response ◽  
Genomic Stability ◽  
Damage Response

scholarly journals Dancing with the DNA damage response: next-generation anti-cancer therapeutic strategies

2018 ◽  
Vol 10 ◽  
pp. 175883591878665 ◽  
Author(s):  
Anna Minchom ◽  
Caterina Aversa ◽  
Juanita Lopez
Keyword(s):  
Cell Cycle ◽  
Immune Response ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Synthetic Lethality ◽  
Parp Inhibitor ◽  
Genomic Stability ◽  
Critical Determinant ◽  
Potential Biomarker ◽  
Damage Response

Maintenance of genomic stability is a critical determinant of cell survival and relies on the coordinated action of the DNA damage response (DDR), which orchestrates a network of cellular processes, including DNA replication, DNA repair and cell-cycle progression. In cancer, the critical balance between the loss of genomic stability in malignant cells and the DDR provides exciting therapeutic opportunities. Drugs targeting DDR pathways taking advantage of clinical synthetic lethality have already shown therapeutic benefit – for example, the PARP inhibitor olaparib has shown benefit in BRCA-mutant ovarian and breast cancer. Olaparib has also shown benefit in metastatic prostate cancer in DDR-defective patients, expanding the potential biomarker of response beyond BRCA. Other agents and combinations aiming to block the DDR while pushing damaged DNA through the cell cycle, including PARP, ATR, ATM, CHK and DNA-PK inhibitors, are in development. Emerging work is also uncovering how the DDR interacts intimately with the host immune response, including by activating the innate immune response, further suggesting that clinical applications together with immunotherapy may be beneficial. Here, we review recent considerations related to the DDR from a clinical standpoint, providing a framework to address future directions and clinical opportunities.

scholarly journals DNA Damage Response-Independent Role for MDC1 in Maintaining Genomic Stability

2017 ◽  
Vol 37 (9) ◽  
Author(s):  
Zhiguo Li ◽  
Chen Shao ◽  
Yifan Kong ◽  
Colin Carlock ◽  
Nihal Ahmad ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Dna Damage Response ◽  
Significant Role ◽  
Elevated Level ◽  
Genomic Stability ◽  
Mitotic Progression ◽  
Checkpoint Activation ◽  
Damage Response

ABSTRACT MDC1 is a central player in checkpoint activation and subsequent DNA repair following DNA damage. Although MDC1 has been studied extensively, many of its known functions, to date, pertain to the DNA damage response (DDR) pathway. Herein we report a novel function of phosphorylated MDC1 that is independent of ATM and DNA damage and is required for proper mitotic progression and maintenance of genomic stability. We demonstrate that MDC1 is an in vivo target of Plk1 and that phosphorylated MDC1 is dynamically localized to nuclear envelopes, centrosomes, kinetochores, and midbodies. Knockdown of MDC1 or abrogation of Plk1 phosphorylation of MDC1 causes a delay of the prometaphase-metaphase transition. It is significant that mice with reduced levels of MDC1 showed an elevated level of spontaneous tumors in aged animals. Our results demonstrate that MDC1 also plays a fundamentally significant role in maintenance of genomic stability through a DDR-independent pathway.

scholarly journals Roles of GOLPH3, a PI(4)P binding protein, in the physiopathology of cancer

2020 ◽  
Author(s):  
Maria Grazia Giansanti ◽  
Roberto Piergentili ◽  
Angela Karimpour Ghahnavieh ◽  
Anna Frappaolo ◽  
Stefano Sechi
Keyword(s):  
Dna Damage ◽  
Plasma Membrane ◽  
Dna Damage Response ◽  
Membrane Trafficking ◽  
Poor Prognosis ◽  
Genomic Stability ◽  
Damage Response ◽  
Ribbon Structure ◽  
Phosphatidylinositol 4 ◽  
Tumor Types

Golgi phosphoprotein 3 (GOLPH3), a Phosphatidylinositol 4-Phosphate [PI(4)P] effector at the Golgi, is required for several intracellular functions, including Golgi ribbon structure maintenance, Golgi glycosylation and vesicle trafficking. It is amplified in several solid tumor types and its overexpression correlates with poor prognosis. GOLPH3 influences tumorigenesis through (i) regulation of Golgi-to-plasma membrane trafficking; (ii) turnover and glycosylation of cancer-relevant glycoproteins; (iii) influence on DNA damage response and maintenance of genomic stability.

scholarly journals Function and Molecular Mechanism of the DNA Damage Response in Immunity and Cancer Immunotherapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Zu Ye ◽  
Yin Shi ◽  
Susan P. Lees-Miller ◽  
John A. Tainer
Keyword(s):  
Dna Damage ◽  
Immune Responses ◽  
Cancer Immunotherapy ◽  
Dna Damage Response ◽  
Immune Checkpoint ◽  
B Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Dna Damage And Repair ◽  
Damage Response

The DNA damage response (DDR) is an organized network of multiple interwoven components evolved to repair damaged DNA and maintain genome fidelity. Conceptually the DDR includes damage sensors, transducer kinases, and effectors to maintain genomic stability and accurate transmission of genetic information. We have recently gained a substantially improved molecular and mechanistic understanding of how DDR components are interconnected to inflammatory and immune responses to stress. DDR shapes both innate and adaptive immune pathways: (i) in the context of innate immunity, DDR components mainly enhance cytosolic DNA sensing and its downstream STimulator of INterferon Genes (STING)-dependent signaling; (ii) in the context of adaptive immunity, the DDR is needed for the assembly and diversification of antigen receptor genes that is requisite for T and B lymphocyte development. Imbalances between DNA damage and repair impair tissue homeostasis and lead to replication and transcription stress, mutation accumulation, and even cell death. These impacts from DDR defects can then drive tumorigenesis, secretion of inflammatory cytokines, and aberrant immune responses. Yet, DDR deficiency or inhibition can also directly enhance innate immune responses. Furthermore, DDR defects plus the higher mutation load in tumor cells synergistically produce primarily tumor-specific neoantigens, which are powerfully targeted in cancer immunotherapy by employing immune checkpoint inhibitors to amplify immune responses. Thus, elucidating DDR-immune response interplay may provide critical connections for harnessing immunomodulatory effects plus targeted inhibition to improve efficacy of radiation and chemotherapies, of immune checkpoint blockade, and of combined therapeutic strategies.

scholarly journals The Cyclin K/Cdk12 complex maintains genomic stability via regulation of expression of DNA damage response genes

2011 ◽  
Vol 25 (20) ◽  
pp. 2158-2172 ◽  
Author(s):  
D. Blazek ◽  
J. Kohoutek ◽  
K. Bartholomeeusen ◽  
E. Johansen ◽  
P. Hulinkova ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Genomic Stability ◽  
Regulation Of Expression ◽  
Damage Response

scholarly journals IDH1R132H acts as a tumor suppressor in glioma via epigenetic upregulation of the DNA damage response

2018 ◽  
Author(s):  
Felipe J. Núñez ◽  
Flor M. Mendez ◽  
Padma Kadiyala ◽  
Mahmoud S. Alghamri ◽  
Masha G. Savelieff ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Tumor Suppressor ◽  
Dna Damage Response ◽  
Genomic Stability ◽  
Isocitrate Dehydrogenase 1 ◽  
Damage Response ◽  
Mutant Idh1 ◽  
Atm Signaling ◽  
The Impact

One sentence summaryMutant IDH1 acts as a tumor suppressor when co-expressed together with TP53 and ATRX inactivating mutations in glioma, inducing genomic stability, DNA repair and resistance to genotoxic therapies.AbstractGlioma patients whose tumors carry a mutation in the Isocitrate Dehydrogenase 1 (IDH1R132H) gene are younger at the time of diagnosis and survive longer. The molecular glioma subtype which we modelled, harbors IDH1R132H, tumor protein 53 (TP53) and alpha-thalassemia/mental retardation syndrome X-linked (ATRX) loss. The impact of IDH1R132H on genomic stability, DNA damage response (DDR) and DNA repair in this molecular glioma subtype is unknown. We discovered that IDH1R132H expression in the genetic context of ATRX and TP53 inactivation: (i) increases median survival (MS), (ii) enhances DDR activity via epigenetic upregulation of Ataxia-telangiectasia mutated (ATM) signaling, and (iii) elicits tumor radioresistance. Pharmacological inhibition of ATM or checkpoint kinase 1 and 2 (CHK1/2), two essential kinases in the DDR pathways, restored tumors’ radiosensitivity. Translation of these findings for mlDH1 glioma patients could significantly improve the therapeutic efficacy of radiotherapy, and thus have a major impact on patient survival.

scholarly journals DNA Damage Response and Cell Cycle Regulation in Pluripotent Stem Cells

Genes ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 1548
Author(s):  
Andy Chun Hang Chen ◽  
Qian Peng ◽  
Sze Wan Fong ◽  
Kai Chuen Lee ◽  
William Shu Biu Yeung ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Pluripotent Stem Cells ◽  
Embryonic Stem ◽  
Genomic Stability ◽  
Great Promise ◽  
Cell Based Therapy ◽  
Damage Response

Pluripotent stem cells (PSCs) hold great promise in cell-based therapy because of their pluripotent property and the ability to proliferate indefinitely. Embryonic stem cells (ESCs) derived from inner cell mass (ICM) possess unique cell cycle control with shortened G1 phase. In addition, ESCs have high expression of homologous recombination (HR)-related proteins, which repair double-strand breaks (DSBs) through HR or the non-homologous end joining (NHEJ) pathway. On the other hand, the generation of induced pluripotent stem cells (iPSCs) by forced expression of transcription factors (Oct4, Sox2, Klf4, c-Myc) is accompanied by oxidative stress and DNA damage. The DNA repair mechanism of DSBs is therefore critical in determining the genomic stability and efficiency of iPSCs generation. Maintaining genomic stability in PSCs plays a pivotal role in the proliferation and pluripotency of PSCs. In terms of therapeutic application, genomic stability is the key to reducing the risks of cancer development due to abnormal cell replication. Over the years, we and other groups have identified important regulators of DNA damage response in PSCs, including FOXM1, SIRT1 and PUMA. They function through transcription regulation of downstream targets (P53, CDK1) that are involved in cell cycle regulations. Here, we review the fundamental links between the PSC-specific HR process and DNA damage response, with a focus on the roles of FOXM1 and SIRT1 on maintaining genomic integrity.

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