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Nature Structural & Molecular Biology May 2024The recognition that DNA can be ADP ribosylated provides an unexpected regulatory level of how ADP-ribosylation contributes to genome stability, epigenetics and...
The recognition that DNA can be ADP ribosylated provides an unexpected regulatory level of how ADP-ribosylation contributes to genome stability, epigenetics and immunity. Yet, it remains unknown whether DNA ADP-ribosylation (DNA-ADPr) promotes genome stability and how it is regulated. Here, we show that telomeres are subject to DNA-ADPr catalyzed by PARP1 and removed by TARG1. Mechanistically, we show that DNA-ADPr is coupled to lagging telomere DNA strand synthesis, forming at single-stranded DNA present at unligated Okazaki fragments and on the 3' single-stranded telomere overhang. Persistent DNA-linked ADPr, due to TARG1 deficiency, eventually leads to telomere shortening. Furthermore, using the bacterial DNA ADP-ribosyl-transferase toxin to modify DNA at telomeres directly, we demonstrate that unhydrolyzed DNA-linked ADP-ribose compromises telomere replication and telomere integrity. Thus, by identifying telomeres as chromosomal targets of PARP1 and TARG1-regulated DNA-ADPr, whose deregulation compromises telomere replication and integrity, our study highlights and establishes the critical importance of controlling DNA-ADPr turnover for sustained genome stability.
Topics: Telomere; ADP-Ribosylation; DNA Replication; Poly (ADP-Ribose) Polymerase-1; Humans; DNA; Animals; Mice; Adenosine Diphosphate Ribose; Genomic Instability; Telomere Shortening
PubMed: 38714889
DOI: 10.1038/s41594-024-01279-6 -
Nature Structural & Molecular Biology May 2024
Topics: Telomere; Humans; DNA; Adenosine Diphosphate; Telomerase
PubMed: 38714888
DOI: 10.1038/s41594-024-01285-8 -
Biomeditsinskaia Khimiia Apr 2024Platelet functional activity was assessed in healthy volunteers (HV, n=92), patients with stable angina pectoris (SA, n=42) and acute coronary syndrome (ACS, n=73),...
Assessment of platelet functional activity in healthy individuals and patients receiving antiplatelet therapy. Possible inconsistencies between aggregation and flow cytometry tests.
Platelet functional activity was assessed in healthy volunteers (HV, n=92), patients with stable angina pectoris (SA, n=42) and acute coronary syndrome (ACS, n=73), treated with acetylsalicylic acid (ASA) + clopidogrel and ASA + ticagrelor, respectively. In all HV and patients we have compared parameters of platelet aggregation (maximum light transmission and velocity, Tmax and Vmax) and parameters, characterizing exposure of platelet activation markers, evaluated by flow cytometry. HV platelets were activated by 10 μM, 1 μM TRAP, and 20 μM, 5 μM, 2.5 μM ADP; patient platelets were activated by 10 μM TRAP and by 20 μM and 5 μM ADP. Strong and significant correlations between the aggregation and flow cytometry parameters (the r correlation coefficient from 0.4 up to >0.6) most frequently were registered in HV platelet during activation by 1 μM TRAP and in SA patients during platelet activation by 20 μM and 5 μM ADP. However, in many other cases these correlations were rather weak (r < 0.3) and sometimes statistically insignificant. In HV the differences in PAC-1 binding parameters between platelets activated by 10 μM TRAP (the strongest agonist) and all ADP concentrations were negligible (≤ 10%), while CD62P binding (at all ADP concentrations) and LTA parameters for (5 μM and 2.5 μM ADP) were significantly lower (by 40-60%). Antiplatelet therapy in patients decreased all parameters as compared to HV, but to varying extents. For 10 μM TRAP the MFI index for PAC-1 binding (40-50% decrease) and for both ADP concentrations the Tmax values (60-85% decrease) appeared to be the most sensitive in comparison with the other parameters that decreased to a lesser extent. The data obtained indicate a possibility of inconsistency between different LTA and flow cytometry parameters in assessing platelet activity and efficacy of antiplatelet drugs.
Topics: Humans; Platelet Aggregation Inhibitors; Flow Cytometry; Platelet Aggregation; Male; Aspirin; Female; Blood Platelets; Middle Aged; Clopidogrel; Aged; Acute Coronary Syndrome; Adult; Ticagrelor; Platelet Function Tests; Platelet Activation; Angina, Stable; Adenosine Diphosphate
PubMed: 38711409
DOI: 10.18097/PBMC20247002099 -
Indian Journal of Hematology & Blood... Apr 2024To determine whether there is higher degree of platelet and/ or coagulation activation in sickle cell anaemia (SS) patients in complications and with clinical risk...
To determine whether there is higher degree of platelet and/ or coagulation activation in sickle cell anaemia (SS) patients in complications and with clinical risk factors. A cross sectional study was conducted at a tertiary health care centre in central India with study groups: sickle cell disease (SCD): sickle cell anaemia (SS) and sickle cell trait (AS) consisting of 100 subjects each and controls (AA) with 40 subjects. Platelet aggregation (PA) with ADP, collagen and epinephrine, PT and aPTT were performed in all subjects and PA with ristocetin in ten candidates of each group. ANOVA and student's unpaired t test were used to compare PA and coagulation profile of the three groups with respect to age groups, gender, present diagnosis, history of complications, frequency of hospital admissions (high ≥ 3/year) and frequency of blood transfusion (high > 2/year). The max PA% with ADP was significantly less in SS patients in steady state, which was even lesser in those having symptoms, complications in past/ present, high-frequency hospital admission and > 2 blood transfusions per year subgroups, as compared to all other groups and subgroups, but not consistently with collagen and epinephrine. The max PA % with ristocetin was least in SS with complications. No statistically significant difference in PT and aPTT values among the various clinical risk subgroups and groups was found. SCD patients can be monitored by using PA with ADP for their timely and better management. PA with ADP, PT and aPTT should be added to the workup of these patients for improved prognostication.
PubMed: 38708151
DOI: 10.1007/s12288-023-01703-9 -
Arab Journal of Gastroenterology : the... May 2024There are limited data regarding indeterminate acute liver failure (ALF). The study aims to perform a post hoc analysis using genetic methods for the ALF cases with...
BACKGROUND AND STUDY AIMS
There are limited data regarding indeterminate acute liver failure (ALF). The study aims to perform a post hoc analysis using genetic methods for the ALF cases with indeterminate etiology.
PATIENTS AND METHODS
Stored blood samples from these patients with indeterminate ALF were collected. Whole-exome sequencing (WES) was used to evaluate the pathogenesis of indeterminate ALF.
RESULTS
A total of 16 samples from 11 adult patients and 5 pediatric patients with indeterminate ALF were available. Among the adult patients, one female patient was identified with two heterozygous variants (c.2333G > T (p.Arg778Leu) and c.2310C > G (p.Leu770 = )) in the adenosine triphosphatase copper-transporting beta (ATP7B) gene, and two male patients were found to harbor heterozygous and homozygous variants (c.686C > A (p.Pro229Gln) plus homozygousvariantA(TA)6TAAinsTA (-), andc.1456 T > G (p.Tyr486Asp) plus c.211G > A (p.Gly71Arg)) in the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene. For the pediatric patients, single heterozygous variant (c.2890C > T (p.Arg964Cys)) in the polymerase gamma (POLG) gene was found in 1 male child, and two heterozygous variants (c.1909A > G (p.Lys637Glu) and c.3646G > A (p.Val1216Ile)) in the tetratricopeptide repeat domain 37 (TTC37) gene were found in 1 female child. No variants clinically associated with known liver diseases were revealed in the remaining patients.
CONCLUSION
These results expand the knowledge of ALF with indeterminate etiology. WES is helpful to reveal possible candidate genes for indeterminate ALF, but incomplete consistency between the genotype and phenotype in some cases still challenge the accurate diagnosis.
Topics: Humans; Liver Failure, Acute; Male; Female; Exome Sequencing; Adult; Glucuronosyltransferase; Child; Copper-Transporting ATPases; Heterozygote; Adolescent; Middle Aged; Child, Preschool; Young Adult; Mutation; Homozygote
PubMed: 38705812
DOI: 10.1016/j.ajg.2024.03.004 -
European Journal of Surgical Oncology :... Jul 2024To evaluate the impact of previous poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor therapy on the effectiveness of secondary cytoreductive surgery (SCS)...
Outcomes of secondary cytoreductive surgery in patients with platinum-sensitive recurrent ovarian cancer progressed after prior poly (adenosine diphosphate-ribose) polymerase inhibitors: A retrospective cohort study.
OBJECTIVE
To evaluate the impact of previous poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor therapy on the effectiveness of secondary cytoreductive surgery (SCS) in patients with platinum-sensitive recurrent ovarian cancer (PSROC).
METHODS
We identified patients with PSROC who underwent SCS at the Cancer Hospital, Chinese Academy of Medical Science, between January 2010 and December 2022. Postoperative complications within 30 days were categorized using the Accordion Severity Grading System. The Kaplan‒Meier method was used to estimate both overall survival (OS) and progression-free survival (PFS), and multivariate analysis was used to identify independent prognostic factors.
RESULTS
Of the 265 patients included, 39 received prior PARP inhibitor therapy (Group A), and 226 did not (Group B). The rates of complete resection after SCS did not significantly differ between the two groups (79.5 % for Group A vs. 81.0 % for Group B; p = 0.766). As of December 2023, Group A exhibited a significantly shorter median PFS (14.2 months) than Group B (22.5 months; p = 0.002). Furthermore, the 3-year OS rate was lower in Group A (72.5 %) than in Group B (82.7 %; p = 0.015). The incidence of severe postoperative complications was comparable between Groups A and B (7.7 % vs. 1.8 %; p = 0.061). Multivariate analysis revealed that prior PARP inhibitor therapy significantly reduced the median PFS (hazard ratio (HR) = 4.434; p = 0.021) and OS (HR = 2.076; p = 0.010).
CONCLUSIONS
SCS for PSROC demonstrated reduced efficacy in patients previously treated with PARP inhibitors compared to those without prior PARP inhibitor treatment.
Topics: Humans; Female; Poly(ADP-ribose) Polymerase Inhibitors; Middle Aged; Retrospective Studies; Ovarian Neoplasms; Cytoreduction Surgical Procedures; Neoplasm Recurrence, Local; Aged; Adult; Survival Rate; Progression-Free Survival; Postoperative Complications
PubMed: 38704898
DOI: 10.1016/j.ejso.2024.108383 -
Thrombosis Research Jun 2024Previous research has identified intravascular platelet thrombi in regions affected by myocardial ischemia-reperfusion (MI/R) injury and neighbouring areas. However, the...
Myocardial ischemia-reperfusion injury released cellular fibronectin containing domain A (CFN-EDA): A destructive positive loop amplifying arterial thrombosis formation and exacerbating myocardial reperfusion injury.
Previous research has identified intravascular platelet thrombi in regions affected by myocardial ischemia-reperfusion (MI/R) injury and neighbouring areas. However, the occurrence of arterial thrombosis in the context of MI/R injury remains unexplored. This study utilizes intravital microscopy to investigate carotid artery thrombosis during MI/R injury in rats, establishing a connection with the presence of prothrombotic cellular fibronectin containing extra domain A (CFN-EDA) protein. Additionally, the study examines samples from patients with coronary artery disease (CAD) both before and after coronary artery bypass grafting (CABG). Levels of CFN-EDA significantly increase following MI with further elevation observed following reperfusion of the ischemic myocardium. Thrombotic events, such as thrombus formation and growth, show a significant increase, while the time to complete cessation of blood flow in the carotid artery significantly decreases following MI/R injury induced by ferric chloride. The acute infusion of purified CFN-EDA protein accelerates in-vivo thrombotic events in healthy rats and significantly enhances in-vitro adenosine diphosphate and collagen-induced platelet aggregation. Treatment with anti-CFN-EDA antibodies protected the rat against MI/R injury and significantly improved cardiac function as evidenced by increased end-systolic pressure-volume relationship slope and preload recruitable stroke work compared to control. Similarly, in a human study, plasma CFN-EDA levels were notably elevated in CAD patients undergoing CABG. Post-surgery, these levels continued to rise over time, alongside cardiac injury biomarkers such as cardiac troponin and B-type natriuretic peptide. The study highlights that increased CFN-EDA due to CAD or MI initiates a destructive positive feedback loop by amplifying arterial thrombus formation, potentially exacerbating MI/R injury.
Topics: Animals; Myocardial Reperfusion Injury; Rats; Humans; Male; Thrombosis; Fibronectins; Rats, Sprague-Dawley; Female; Middle Aged; Coronary Artery Disease; Aged
PubMed: 38703585
DOI: 10.1016/j.thromres.2024.04.026 -
Journal of Food Protection Jul 2024Given its presence in a wide spectrum of soils relevant to food process hygiene, the biological metabolite adenosine triphosphate (ATP) is used as a target for surface...
Given its presence in a wide spectrum of soils relevant to food process hygiene, the biological metabolite adenosine triphosphate (ATP) is used as a target for surface hygiene assessments in food processing facilities. Yet, ample evidence demonstrates that ATP is depleted into adenosine di- (ADP) and monophosphate (AMP) homologs resulting in a loss of sensitivity for ATP-based hygiene assays. Yet, there are few studies that denote the degree of these shifts under routine processing conditions such as those encountered during various meat processing steps that may likely alter redox potential and adenosine profiles (e.g., tissue/cellular disruption, application of reducing additives, fermentation, or thermal treatment steps). In this study, meat samples were collected from homogenized beef tissue treated with nonmeat ingredients (sodium chloride, sodium nitrite, sodium erythorbate, natural smoke condensate, and sodium acid pyrophosphate) during manufacture at predetermined steps, and from retail meat products purchased from local markets. Concentrations of ATP, ADP, AMP, and AXP (sum concentration of all homologs) in a lab setting and in situ meat processing venues were determined and compared. Greater differences in AXP were seen during manufacture, where ADP generally comprised ∼90% as a mole fraction of AXP across all treatments, with the exception of the final cook step where AMP predominated. ATP concentrations averaged 2 log values lower than ADP and AMP. Adenosine profiles in retail samples followed similar trends with minimal ATP concentrations with ADP predominant in uncooked samples and AMP predominant in cooked samples. Resultingly, meat processing steps during product manufacture will alter AXP-reliant test sensitivities which should be considered when such technologies are utilized for hygiene verification in meat processing.
Topics: Adenosine Triphosphate; Food Handling; Animals; Meat; Adenosine Diphosphate; Adenosine Monophosphate; Food Contamination; Cattle; Humans; Meat Products
PubMed: 38697482
DOI: 10.1016/j.jfp.2024.100287 -
International Journal of Biological... Jun 2024The sarco/endoplasmic reticulum Ca-ATPase (SERCA) transports two Ca ions per ATP hydrolyzed from the cytoplasm to the lumen. However, how the ATP hydrolysis remotely...
The sarco/endoplasmic reticulum Ca-ATPase (SERCA) transports two Ca ions per ATP hydrolyzed from the cytoplasm to the lumen. However, how the ATP hydrolysis remotely drives the Ca transport is unclear. In the SERCA1a crystal structures, the ATP hydrolysis is accompanied by the notably increasing tilting angle of the central core (CC) and the Ca transport, and the CC tilting angle dramatically decreases in the E2 to E1 transition. We demonstrated that the significantly increasing tilting motion of the CC drove the Ca release in the molecular dynamics simulation of the R836A variant, and the dramatic spontaneous decrease in the CC tilting angle of the E2 state triggers the restart of the SERCA1a's transport cycle. The repulsion between the phosphorylated D351 and the phosphate groups in ADP triggers the release of ADP from the SERCA1a headpiece. We proposed a novel SERCA transport mechanism in which ATP hydrolysis drives a significant tilting motion of the CC, which drives Ca transport and the A domain rotational motion in the E1P-ADP-2Ca to E2P transition. The dramatic spontaneous decrease in the CC tilting angle of the E2 state drives the restart of the transport cycle.
Topics: Sarcoplasmic Reticulum Calcium-Transporting ATPases; Calcium; Adenosine Triphosphate; Molecular Dynamics Simulation; Hydrolysis; Adenosine Diphosphate; Humans; Biological Transport
PubMed: 38697445
DOI: 10.1016/j.ijbiomac.2024.132000