scholarly journals Biallelic ADPRHL2 mutations in complex neuropathy affect ADP ribosylation and DNA damage response

2021 ◽  
Vol 4 (11) ◽  
pp. e202101057
Author(s):  
Danique Beijer ◽  
Thomas Agnew ◽  
Johannes Gregor Matthias Rack ◽  
Evgeniia Prokhorova ◽  
Tine Deconinck ◽  
...  
Keyword(s):  
Dna Damage ◽  
Protein Function ◽  
Damage Control ◽  
Axonal Neuropathy ◽  
Vital Role ◽  
Adp Ribosylation ◽  
Function Characterization ◽  
Ataxia Syndrome ◽  
Protein Instability

ADP ribosylation is a reversible posttranslational modification mediated by poly(ADP-ribose)transferases (e.g., PARP1) and (ADP-ribosyl)hydrolases (e.g., ARH3 and PARG), ensuring synthesis and removal of mono-ADP-ribose or poly-ADP-ribose chains on protein substrates. Dysregulation of ADP ribosylation signaling has been associated with several neurodegenerative diseases, including Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease. Recessive ADPRHL2/ARH3 mutations are described to cause a stress-induced epileptic ataxia syndrome with developmental delay and axonal neuropathy (CONDSIAS). Here, we present two families with a neuropathy predominant disorder and homozygous mutations in ADPRHL2. We characterized a novel C26F mutation, demonstrating protein instability and reduced protein function. Characterization of the recurrent V335G mutant demonstrated mild loss of expression with retained enzymatic activity. Although the V335G mutation retains its mitochondrial localization, it has altered cytosolic/nuclear localization. This minimally affects basal ADP ribosylation but results in elevated nuclear ADP ribosylation during stress, demonstrating the vital role of ADP ribosylation reversal by ARH3 in DNA damage control.

scholarly journals PPM1G promotes the progression of hepatocellular carcinoma via phosphorylation regulation of alternative splicing protein SRSF3

2021 ◽  
Vol 12 (8) ◽  
Author(s):  
Dawei Chen ◽  
Zhenguo Zhao ◽  
Lu Chen ◽  
Qinghua Li ◽  
Jixue Zou ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Alternative Splicing ◽  
Protein Function ◽  
Vital Role ◽  
Normal Tissues ◽  
Mechanistic Analysis ◽  
Highly Correlated ◽  
Splicing Patterns

AbstractEmerging evidence has demonstrated that alternative splicing has a vital role in regulating protein function, but how alternative splicing factors can be regulated remains unclear. We showed that the PPM1G, a protein phosphatase, regulated the phosphorylation of SRSF3 in hepatocellular carcinoma (HCC) and contributed to the proliferation, invasion, and metastasis of HCC. PPM1G was highly expressed in HCC tissues compared to adjacent normal tissues, and higher levels of PPM1G were observed in adverse staged HCCs. The higher levels of PPM1G were highly correlated with poor prognosis, which was further validated in the TCGA cohort. The knockdown of PPM1G inhibited the cell growth and invasion of HCC cell lines. Further studies showed that the knockdown of PPM1G inhibited tumor growth in vivo. The mechanistic analysis showed that the PPM1G interacted with proteins related to alternative splicing, including SRSF3. Overexpression of PPM1G promoted the dephosphorylation of SRSF3 and changed the alternative splicing patterns of genes related to the cell cycle, the transcriptional regulation in HCC cells. In addition, we also demonstrated that the promoter of PPM1G was activated by multiple transcription factors and co-activators, including MYC/MAX and EP300, MED1, and ELF1. Our study highlighted the essential role of PPM1G in HCC and shed new light on unveiling the regulation of alternative splicing in malignant transformation.

scholarly journals ARF induction in response to DNA strand breaks is regulated by PARP1

2013 ◽  
Vol 42 (4) ◽  
pp. 2320-2329 ◽  
Author(s):  
Giulia Orlando ◽  
Svetlana V. Khoronenkova ◽  
Irina I. Dianova ◽  
Jason L. Parsons ◽  
Grigory L. Dianov
Keyword(s):  
Dna Damage ◽  
Protein Function ◽  
P53 Protein ◽  
Dna Strand Breaks ◽  
Vital Role ◽  
Cellular Stress Response ◽  
Strand Breaks ◽  
Dna Strand ◽  
Cellular Dna ◽  
Arf Protein

Abstract The ARF tumour suppressor protein, the gene of which is frequently mutated in many human cancers, plays an important role in the cellular stress response by orchestrating up-regulation of p53 protein and consequently promoting cell-cycle delay. Although p53 protein function has been clearly linked to the cellular DNA damage response, the role of ARF protein in this process is unclear. Here, we report that arf gene transcription is induced by DNA strand breaks (SBs) and that ARF protein accumulates in response to persistent DNA damage. We discovered that poly(ADP-ribose) synthesis catalysed by PARP1 at the sites of unrepaired SBs activates ARF transcription through a protein signalling cascade, including the NAD+-dependent deacetylase SIRT1 and the transcription factor E2F1. Our data suggest that poly(ADP-ribose) synthesis at the sites of SBs initiates DNA damage signal transduction by reducing the cellular concentration of NAD+, thus down-regulating SIRT1 activity and consequently activating E2F1-dependent ARF transcription. Our findings suggest a vital role for ARF in DNA damage signalling, and furthermore explain the critical requirement for ARF inactivation in cancer cells, which are frequently deficient in DNA repair and accumulate DNA damage.

miR-424/322 is downregulated in the semen of patients with severe DNA damage and may regulate sperm DNA damage

2016 ◽  
Vol 28 (10) ◽  
pp. 1598 ◽  
Author(s):  
Kai Zhao ◽  
Yaoping Chen ◽  
Ruifeng Yang ◽  
Yang Bai ◽  
Cuiling Li ◽  
...  
Keyword(s):  
Dna Damage ◽  
Human Sperm ◽  
Vital Role ◽  
Dna Integrity ◽  
Dna Double Strand Breaks ◽  
Human Seminal Plasma ◽  
Sperm Dna Damage ◽  
Sperm Dna ◽  
Murine Homologue

Sperm DNA integrity is an essential factor for accurate transmission of genetic information. Human sperm DNA damage is a common cause of male infertility but the exact mechanism remains poorly understood. Considering the vital role of microRNA (miRNA) in multiple pathophysiological processes, we hypothesised that testicular miRNA is involved in sperm DNA damage during spermatogenesis. Infertile patients with high sperm DNA fragment index (DFI; n = 94) were selected from 1090 infertile men and a total of 18 testis-specific seminal miRNAs previously identified from human seminal plasma were chosen and tested. miR-29c and miR-424 were downregulated in men with high DFI. The inhibition of these two miRNAs in mice confirmed the role of miR-424 (murine homologue miR-322) in sperm DNA damage during spermatogenesis; by contrast, miR-29c exhibited a negative result. Thus, miR-424/322 is involved in sperm DNA damage. Furthermore, the dysregulation of this miRNA can induce DNA double-strand breaks during spermatogenesis.

scholarly journals The role of poly ADP-ribosylation in the first wave of DNA damage response

2017 ◽  
Vol 45 (14) ◽  
pp. 8129-8141 ◽  
Author(s):  
Chao Liu ◽  
Aditi Vyas ◽  
Muzaffer A. Kassab ◽  
Anup K. Singh ◽  
Xiaochun Yu
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Adp Ribosylation ◽  
Damage Response

scholarly journals Serine-linked PARP1 auto-modification controls PARP inhibitor response

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Evgeniia Prokhorova ◽  
Florian Zobel ◽  
Rebecca Smith ◽  
Siham Zentout ◽  
Ian Gibbs-Seymour ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Dna Repair ◽  
Parp Inhibitor ◽  
Cellular Responses ◽  
Vital Role ◽  
Inhibitor Tolerance ◽  
Adp Ribosylation ◽  
Key Sites ◽  
Dependent Modification

AbstractPoly(ADP-ribose) polymerase 1 (PARP1) and PARP2 are recruited and activated by DNA damage, resulting in ADP-ribosylation at numerous sites, both within PARP1 itself and in other proteins. Several PARP1 and PARP2 inhibitors are currently employed in the clinic or undergoing trials for treatment of various cancers. These drugs act primarily by trapping PARP1 on damaged chromatin, which can lead to cell death, especially in cells with DNA repair defects. Although PARP1 trapping is thought to be caused primarily by the catalytic inhibition of PARP-dependent modification, implying that ADP-ribosylation (ADPr) can counteract trapping, it is not known which exact sites are important for this process. Following recent findings that PARP1- or PARP2-mediated modification is predominantly serine-linked, we demonstrate here that serine ADPr plays a vital role in cellular responses to PARP1/PARP2 inhibitors. Specifically, we identify three serine residues within PARP1 (499, 507, and 519) as key sites whose efficient HPF1-dependent modification counters PARP1 trapping and contributes to inhibitor tolerance. Our data implicate genes that encode serine-specific ADPr regulators, HPF1 and ARH3, as potential PARP1/PARP2 inhibitor therapy biomarkers.

Role of p53 mutations, protein function and DNA damage for the radiosensitivity of human tumour cells

2004 ◽  
Vol 80 (1) ◽  
pp. 53-63 ◽  
Author(s):  
A. Böhnke ◽  
F. Westphal ◽  
A. Schmidt ◽  
R. A. El‐Awady ◽  
J. Dahm‐Daphi
Keyword(s):  
Dna Damage ◽  
Protein Function ◽  
Tumour Cells ◽  
P53 Mutations ◽  
Human Tumour ◽  
Human Tumour Cells

scholarly journals TRIM66 reads unmodified H3R2K4 and H3K56ac to respond to DNA damage in embryonic stem cells

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Jiajing Chen ◽  
Zikang Wang ◽  
Xudong Guo ◽  
Fudong Li ◽  
Qingtao Wei ◽  
...  
Keyword(s):  
Stem Cells ◽  
Dna Damage ◽  
Embryonic Stem Cells ◽  
Critical Role ◽  
Embryonic Stem ◽  
Genomic Stability ◽  
Vital Role ◽  
Damage Repair ◽  
The Relationship

Abstract Recognition of specific chromatin modifications by distinct structural domains within “reader” proteins plays a critical role in the maintenance of genomic stability. However, the specific mechanisms involved in this process remain unclear. Here we report that the PHD-Bromo tandem domain of tripartite motif-containing 66 (TRIM66) recognizes the unmodified H3R2-H3K4 and acetylated H3K56. The aberrant deletion of Trim66 results in severe DNA damage and genomic instability in embryonic stem cells (ESCs). Moreover, we find that the recognition of histone modification by TRIM66 is critical for DNA damage repair (DDR) in ESCs. TRIM66 recruits Sirt6 to deacetylate H3K56ac, negatively regulating the level of H3K56ac and facilitating the initiation of DDR. Importantly, Trim66-deficient blastocysts also exhibit higher levels of H3K56ac and DNA damage. Collectively, the present findings indicate the vital role of TRIM66 in DDR in ESCs, establishing the relationship between histone readers and maintenance of genomic stability.

scholarly journals Serine ADP-ribosylation marks nucleosomes for ALC1-dependent chromatin remodeling

2021 ◽  
Author(s):  
Jugal Mohapatra ◽  
Kyuto Tashiro ◽  
Ryan L Beckner ◽  
Jorge Sierra ◽  
Jessica A Kilgore ◽  
...  
Keyword(s):  
Dna Damage ◽  
Chromatin Remodeling ◽  
Protein Function ◽  
Post Translational Modification ◽  
Site Specific ◽  
Precise Control ◽  
Adp Ribosylation ◽  
Nuclear Extracts ◽  
Biochemical Function ◽  
The Impact

Serine ADP-ribosylation (ADPr) is a DNA damage-induced post-translational modification catalyzed by the PARP1/2:HPF1 complex. As the list of PARP1/2:HPF1 substrates continues to expand, there is a need for technologies to prepare mono- and poly-ADP-ribosylated proteins for biochemical interrogation. Here we investigate the unique peptide ADPr activities catalyzed by PARP1 in the absence and presence of HPF1. We then exploit these activities to develop a method that facilitates installation of ADP-ribose polymers onto full-length proteins with precise control over chain length and modification site. A series of semi-synthetic ADP-ribosylated histone proteins are prepared which demonstrate that ADPr at H2BS6 or H3S10 converts nucleosomes into robust substrates for the chromatin remodeler ALC1. Importantly, we found ALC1 selectively remodels "activated" substrates within heterogeneous nucleosome populations and that nucleosome serine ADPr is sufficient to stimulate ALC1 activity in nuclear extracts. Our study identifies a biochemical function for nucleosome serine ADPr and describes a method that is broadly applicable to explore the impact that site-specific serine mono- and poly-ADPr have on protein function.

Asiana Airlines Flight 214

2014 ◽  
Vol 4 (2) ◽  
pp. 113-121 ◽  
Author(s):  
Stephanie Chow ◽  
Stephen Yortsos ◽  
Najmedin Meshkati
Keyword(s):  
Human Factors ◽  
Aviation Safety ◽  
Cultural Factors ◽  
Vital Role ◽  
Cultural Issues ◽  
Flight Crew ◽  
Pilot Performance ◽  
Engineering Designs ◽  
Flight Deck

This article focuses on a major human factors–related issue that includes the undeniable role of cultural factors and cockpit automation and their serious impact on flight crew performance, communication, and aviation safety. The report concentrates on the flight crew performance of the Boeing 777–Asiana Airlines Flight 214 accident, by exploring issues concerning mode confusion and autothrottle systems. It also further reviews the vital role of cultural factors in aviation safety and provides a brief overview of past, related accidents. Automation progressions have been created in an attempt to design an error-free flight deck. However, to do that, the pilot must still thoroughly understand every component of the flight deck – most importantly, the automation. Otherwise, if pilots are not completely competent in terms of their automation, the slightest errors can lead to fatal accidents. As seen in the case of Asiana Flight 214, even though engineering designs and pilot training have greatly evolved over the years, there are many cultural, design, and communication factors that affect pilot performance. It is concluded that aviation systems designers, in cooperation with pilots and regulatory bodies, should lead the strategic effort of systematically addressing the serious issues of cockpit automation, human factors, and cultural issues, including their interactions, which will certainly lead to better solutions for safer flights.

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