scholarly journals PARP dependent acetylation of N4-cytidine in RNA appeared in UV-damaged chromatin

2021 ◽  
Author(s):  
Alena Kovaříková Svobodová ◽  
Lenka Stixová ◽  
Aleš Kovařík ◽  
Eva Bártová
Keyword(s):  
Dna Damage ◽  
Functional Properties ◽  
Dna Damage Repair ◽  
Dna Lesions ◽  
Regulatory Role ◽  
Rna Modifications ◽  
Damage Repair ◽  
Rna Accumulation ◽  
High Level

Abstract Posttranscriptional RNA modifications, including the presence of methyl-6-adenosine (m6A), methyl-5-cytosine (m5C), or pseudo-uridine (Ψ), are known for over many years, but their functional properties have not been fully elucidated yet. Similarly, the regulatory role of N4-cytidine (ac4C) acetylation in RNA must be explored. Here, we observed PARP-dependent accumulation of ac4C RNA at UVA-microirradiated chromatin, which appears 2-5 minutes after genome injury, simultaneously with m6A RNAs but with distinct kinetics. When m6A RNAs disappeared from the lesions, the high level of ac4C RNA was maintained up to 20 minutes after genome injury. Surprisingly, the process of ac4C RNA accumulation at DNA lesions was not accompanied by the recruitment of acetyltransferase NAT10 to UVA-induced DNA lesions. This process was PARP dependent, and data show how epitranscriptomic features can contribute to DNA damage repair.

scholarly journals Metabolomics Reveals Aging-associated Attenuation of Noninvasive Radiation Biomarkers in Mice: Potential Role of Polyamine Catabolism and Incoherent DNA Damage-repair

2013 ◽  
Vol 12 (5) ◽  
pp. 2269-2281 ◽  
Author(s):  
Soumen K. Manna ◽  
Kristopher W. Krausz ◽  
Jessica A. Bonzo ◽  
Jeffrey R. Idle ◽  
Frank J. Gonzalez
Keyword(s):  
Dna Damage ◽  
Potential Role ◽  
Dna Damage Repair ◽  
Polyamine Catabolism ◽  
Damage Repair

Investigating the Role of SF3B1 Mutations in DNA Damage Repair in Myeloid Malignancies

2017 ◽  
Vol 55 ◽  
pp. S159-S160
Author(s):  
K. Lappin ◽  
F. Liberante ◽  
K. Savage ◽  
K. Mills
Keyword(s):  
Dna Damage ◽  
Dna Damage Repair ◽  
Myeloid Malignancies ◽  
Damage Repair

Abstract 2039: The role of HORMAD1 in DNA damage repair in squamous cell carcinomas

2021 ◽  
Author(s):  
Jennifer Gantchev ◽  
Amelia Martinez Villarreal ◽  
Brandon Ramchatesingh ◽  
Ivan V. Litvinov
Keyword(s):  
Dna Damage ◽  
Squamous Cell ◽  
Dna Damage Repair ◽  
Squamous Cell Carcinomas ◽  
Damage Repair

scholarly journals SIRT7-mediated ATM deacetylation is essential for its deactivation and DNA damage repair

2019 ◽  
Vol 5 (3) ◽  
pp. eaav1118 ◽  
Author(s):  
Ming Tang ◽  
Zhiming Li ◽  
Chaohua Zhang ◽  
Xiaopeng Lu ◽  
Bo Tu ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Repair ◽  
Class Iii ◽  
Ataxia Telangiectasia Mutated ◽  
Damage Repair ◽  
Damage Response ◽  
Late Stages

The activation of ataxia-telangiectasia mutated (ATM) upon DNA damage involves a cascade of reactions, including acetylation by TIP60 and autophosphorylation. However, how ATM is progressively deactivated after completing DNA damage repair remains obscure. Here, we report that sirtuin 7 (SIRT7)–mediated deacetylation is essential for dephosphorylation and deactivation of ATM. We show that SIRT7, a class III histone deacetylase, interacts with and deacetylates ATM in vitro and in vivo. In response to DNA damage, SIRT7 is mobilized onto chromatin and deacetylates ATM during the late stages of DNA damage response, when ATM is being gradually deactivated. Deacetylation of ATM by SIRT7 is prerequisite for its dephosphorylation by its phosphatase WIP1. Consequently, depletion of SIRT7 or acetylation-mimic mutation of ATM induces persistent ATM phosphorylation and activation, thus leading to impaired DNA damage repair. Together, our findings reveal a previously unidentified role of SIRT7 in regulating ATM activity and DNA damage repair.

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 Long noncoding RNA HCP5 participates in premature ovarian insufficiency by transcriptionally regulating MSH5 and DNA damage repair via YB1

2020 ◽  
Vol 48 (8) ◽  
pp. 4480-4491 ◽  
Author(s):  
Xiaoyan Wang ◽  
Xinyue Zhang ◽  
Yujie Dang ◽  
Duan Li ◽  
Gang Lu ◽  
...  
Keyword(s):  
Dna Damage ◽  
Noncoding Rna ◽  
Dna Damage Repair ◽  
Noncoding Rnas ◽  
Epigenetic Mechanism ◽  
Premature Ovarian Insufficiency ◽  
Genetic Etiology ◽  
Ovarian Insufficiency ◽  
Damage Repair

Abstract The genetic etiology of premature ovarian insufficiency (POI) has been well established to date, however, the role of long noncoding RNAs (lncRNAs) in POI is largely unknown. In this study, we identified a down-expressed lncRNA HCP5 in granulosa cells (GCs) from biochemical POI (bPOI) patients, which impaired DNA damage repair and promoted apoptosis of GCs. Mechanistically, we discovered that HCP5 stabilized the interaction between YB1 and its partner ILF2, which could mediate YB1 transferring into the nucleus of GCs. HCP5 silencing affected the localization of YB1 into nucleus and reduced the binding of YB1 to the promoter of MSH5 gene, thereby diminishing MSH5 expression. Taken together, we identified that the decreased expression of HCP5 in bPOI contributed to dysfunctional GCs by regulating MSH5 transcription and DNA damage repair via the interaction with YB1, providing a novel epigenetic mechanism for POI pathogenesis.

Germline and somatic DNA damage repair gene mutations potentially predict the efficacy of relevant treatment in Chinese patients with pancreatic ductal adenocarcinoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16732-e16732
Author(s):  
Lin Shui ◽  
Yang Peng ◽  
Shuangshuang Li ◽  
Jiangfang Tian ◽  
Dan Cao
Keyword(s):  
Dna Damage ◽  
Dna Damage Repair ◽  
Chinese Patients ◽  
Ductal Adenocarcinoma ◽  
Molecular Heterogeneity ◽  
Genetic Characteristics ◽  
Damage Repair ◽  
Potential Biomarker ◽  
Platinum Based Chemotherapy

e16732 Background: PDAC is a fatal disease with molecular heterogeneity, inducing differences in biological behaviour and therapeutic strategy. We conducted a study to reveal the mutation landscape of Chinese PDAC patients, and investigate the predictive role of germline and somatic DNA damage repair (DDR) status in precise treatment. Methods: 195 PDAC patients were enrolled from multiple medical centers of China between Jan 2016 to Nov 2019. Baseline clinical or genetic characteristics, and survival status were collected. NGS were performed on paraffin-embedded resected tissues or peripheral blood using a panel of 417 genes, including 50 DDR-related genes. Survival analysis was conducted using Kaplan-Meier, and Cox proportional hazard regression model. Results: The main driver genes were KRAS, TP53, CDKN2A, and SMAD4. Patients with KRAS mutation showed worse OS than those without (p = 0.048). DDR deficiency were identified in 15.38% of overall patients, mainly occurred in BRCA2 (4.62%), ATM (4.10%), RAD50 (1.54%) and MLH1 genes (1.03%). No significant improvement of OS existed between patients with or without DDR mutations (p = 0.88). Treatment with olaparib (adjusted HR, 0.2550; P = 0.0720) or platinum-based chemotherapy (adjusted HR, 0.1308; P = 0.0185) respectively decreased hazard of death in patients with DDR mutation. Besides BRCA gene, ATM mutant patients treated with olaparib harbored prolonged median OS than those without olaparib treatment (22.25 vs 15.2 month). Despite a little higher PD-L1 expression rate were seen in DDR mutant patients (29.17% vs 20.51%), no statistical correlation between tumor mutation burden level and DDR mutation was identified. And in patients treated with PD-1 blockade, 2 patients of DDR wild-type group both had SD, whereas of the remaining 5 patients with DDR deficiency, 1 was evaluated as PR, 3 as SD, and 1 as PD (ORR, 0 wt vs 20% mut). Conclusions: In this multi-center retrospective study, we deciphered the intra-tumoral genetic heterogeneity in Chinese PDAC population, which differs from western patients cohort to some extent. We found the potential role of germline and somatic DDR mutation status in predicting the response to olaparib and platinum-based chemotherapy, especially with BRCA or ATM mutation. However, DDR alteration was limited in prediction of hypermutational status and sensitivity to PD-1 blockade. Our study may provide a valuable evidence for clinical application of DDR mutation as a potential biomarker for precise treatment.

Effect of inhibition of receptor tyrosine kinase AXL by a selective small molecular inhibitor R428 (BGB321) on DNA damage repair response in ovarian cancer cells.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15640-e15640
Author(s):  
Ruby Yun-Ju Huang ◽  
Xun Hui Yeo ◽  
Wai Leong Tam
Keyword(s):  
Dna Damage ◽  
Tyrosine Kinase ◽  
Cell Lines ◽  
Dna Damage Response ◽  
Receptor Tyrosine Kinase ◽  
Dna Damage Repair ◽  
Damage Repair ◽  
Damage Response ◽  
Dna Damage Responses

e15640 Background: AXL is a receptor tyrosine kinase that is often overexpressed in many cancers. It contributes to tumor progression, metastasis and drug resistance through activating downstream signaling cascades, making it an emerging therapeutic target. The first-in-class AXL inhibitor R428 (BGB321) was approved by the FDA for the treatment of relapsed or refractory acute myeloid leukemia. R428 (BGB321) was also reported to show selective sensitivity towards ovarian cancers (OC) with a Mesenchymal (Mes) molecular subtype. Recently, a novel role of AXL in the regulation of DNA damage responses has been described. In this study, we explored further the role of AXL in mediating DNA damage responses by using OC as a disease model. Methods: OC cell lines were treated with R428. Accumulation of γH2AX positive foci was assessed for DNA damage response. Western blotting for γH2AX, ATM and ATR levels were performed. Dose response curves of ATR inhibitors were generated by treating OC cells with the fixed dose of R428 (IC20 concentration of each cell line). Results: AXL inhibition by using R428 resulted in the increase of DNA damage foci in Mes OC cells SKOV3 and HeyA8. This occurred concurrently with the up-regulation of classic DNA damage response signaling molecules such as γH2AX, ATM and ATR. The IC50 of the ATR inhibitor significantly decreased for 2-3 folds in all OC cell lines tested. AXL inhibitor R428 sensitized both BRCA-mutated and non-BRCA-mutated OC cells to a potent and highly selective ATR inhibitor. Conclusions: Our results showed that AXL inhibition rendered cells more sensitive to the inhibition of ATR, a crucial mediator for replication stress, paving ways to the rationale for potential combinatory use of AXL and DNA damage repair inhibitors.

Sign in / Sign up

Export Citation Format

Share Document