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The EMBO Journal May 2023Homologous recombination (HR) is a key DNA damage repair pathway that is tightly adjusted to the state of a cell. A central regulator of homologous recombination is the...
Homologous recombination (HR) is a key DNA damage repair pathway that is tightly adjusted to the state of a cell. A central regulator of homologous recombination is the conserved helicase-containing Bloom syndrome complex, renowned for its crucial role in maintaining genome integrity. Here, we show that in Arabidopsis thaliana, Bloom complex activity is controlled by selective autophagy. We find that the recently identified DNA damage regulator KNO1 facilitates K63-linked ubiquitination of RMI1, a structural component of the complex, thereby triggering RMI1 autophagic degradation and resulting in increased homologous recombination. Conversely, reduced autophagic activity makes plants hypersensitive to DNA damage. KNO1 itself is also controlled at the level of proteolysis, in this case mediated by the ubiquitin-proteasome system, becoming stabilized upon DNA damage via two redundantly acting deubiquitinases, UBP12 and UBP13. These findings uncover a regulatory cascade of selective and interconnected protein degradation steps resulting in a fine-tuned HR response upon DNA damage.
Topics: Humans; Autophagy; Bloom Syndrome; DNA-Binding Proteins; Homologous Recombination; Proteasome Endopeptidase Complex
PubMed: 36970874
DOI: 10.15252/embj.2022111980 -
Neurobiology of Disease May 2023RecQ helicase family proteins play vital roles in maintaining genome stability, including DNA replication, recombination, and DNA repair. In human cells, there are five...
RecQ helicase family proteins play vital roles in maintaining genome stability, including DNA replication, recombination, and DNA repair. In human cells, there are five RecQ helicases: RECQL1, Bloom syndrome (BLM), Werner syndrome (WRN), RECQL4, and RECQL5. Dysfunction or absence of RecQ proteins is associated with genetic disorders, tumorigenesis, premature aging, and neurodegeneration. The biochemical and biological roles of RecQ helicases are rather well established, however, there is no systematic study comparing the behavioral changes among various RecQ-deficient mice including consequences of exposure to DNA damage. Here, we investigated the effects of ionizing irradiation (IR) on three RecQ-deficient mouse models (RecQ1, WRN and RecQ4). We find abnormal cognitive behavior in RecQ-deficient mice in the absence of IR. Interestingly, RecQ dysfunction impairs social ability and induces depressive-like behavior in mice after a single exposure to IR, suggesting that RecQ proteins play roles in mood and cognition behavior. Further, transcriptomic and metabolomic analyses revealed significant alterations in RecQ-deficient mice, especially after IR exposure. In particular, pathways related to neuronal and microglial functions, DNA damage repair, cell cycle, and reactive oxygen responses were downregulated in the RecQ4 and WRN mice. In addition, increased DNA damage responses were found in RecQ-deficient mice. Notably, two genes, Aldolase Fructose-Bisphosphate B (Aldob) and NADPH Oxidase 4 (Nox4), were differentially expressed in RecQ-deficient mice. Our findings suggest that RecQ dysfunction contributes to social and depressive-like behaviors in mice, and that aldolase activity may be associated with these changes, representing a potential therapeutic target.
Topics: Animals; Humans; Mice; RecQ Helicases; DNA Replication; DNA Repair; DNA Damage; Genomic Instability; Aldehyde-Lyases
PubMed: 36948261
DOI: 10.1016/j.nbd.2023.106092 -
International Journal of Surgery... Mar 2023
Topics: Humans; Bloom Syndrome; Mouth Neoplasms; Precancerous Conditions
PubMed: 36928777
DOI: 10.1097/JS9.0000000000000009 -
Journal of the American College of... Mar 2023
Topics: Humans; Cardiovascular Abnormalities; Loeys-Dietz Syndrome; Subclavian Artery; Marfan Syndrome
PubMed: 36889878
DOI: 10.1016/j.jacc.2023.01.020 -
Journal of the American College of... Mar 2023Discrepancies in cardiovascular care for women are well described, but few data assess the entire patient journey for chest pain care.
BACKGROUND
Discrepancies in cardiovascular care for women are well described, but few data assess the entire patient journey for chest pain care.
OBJECTIVES
This study aimed to assess sex differences in epidemiology and care pathways from emergency medical services (EMS) contact through to clinical outcomes following discharge.
METHODS
This is a state-wide population-based cohort study including consecutive adult patients attended by EMS for acute undifferentiated chest pain in Victoria, Australia (January 1, 2015, to June 30, 2019). EMS clinical data were individually linked to emergency and hospital administrative datasets, and mortality data and differences in care quality and outcomes were assessed using multivariable analyses.
RESULTS
In 256,901 EMS attendances for chest pain, 129,096 attendances (50.3%) were women, and mean age was 61.6 years. Age-standardized incidence rates were marginally higher for women compared with men (1,191 vs 1,135 per 100,000 person-years). In multivariable models, women were less likely to receive guideline-directed care across most care measures including transport to hospital, prehospital aspirin or analgesia administration, 12-lead electrocardiogram, intravenous cannula insertion, and off-load from EMS or review by emergency department clinicians within target times. Similarly, women with acute coronary syndrome were less likely to undergo angiography or be admitted to a cardiac or intensive care unit. Thirty-day and long-term mortality was higher for women diagnosed with ST-segment elevation myocardial infarction, but lower overall.
CONCLUSIONS
Substantial differences in care are present across the spectrum of acute chest pain management from first contact through to hospital discharge. Women have higher mortality for STEMI, but better outcomes for other etiologies of chest pain compared with men.
Topics: Adult; Humans; Female; Male; Middle Aged; Cohort Studies; Sex Characteristics; Chest Pain; Emergency Medical Services; ST Elevation Myocardial Infarction; Victoria
PubMed: 36889871
DOI: 10.1016/j.jacc.2022.12.025 -
The Journal of Pediatrics Dec 2023To describe the clinical presentation, management, and outcomes of Kawasaki disease (KD) in Latin America and to evaluate early prognostic indicators of coronary artery... (Observational Study)
Observational Study
OBJECTIVES
To describe the clinical presentation, management, and outcomes of Kawasaki disease (KD) in Latin America and to evaluate early prognostic indicators of coronary artery aneurysm (CAA).
STUDY DESIGN
An observational KD registry-based study was conducted in 64 participating pediatric centers across 19 Latin American countries retrospectively between January 1, 2009, and December 31, 2013, and prospectively from June 1, 2014, to May 31, 2017. Demographic and initial clinical and laboratory data were collected. Logistic regression incorporating clinical factors and maximum coronary artery z-score at initial presentation (between 10 days before and 5 days after intravenous immunoglobulin [IVIG]) was used to develop a prognostic model for CAA during follow-up (>5 days after IVIG).
RESULTS
Of 1853 patients with KD, delayed admission (>10 days after fever onset) occurred in 16%, 25% had incomplete KD, and 11% were resistant to IVIG. Among 671 subjects with reported coronary artery z-score during follow-up (median: 79 days; IQR: 36, 186), 21% had CAA, including 4% with giant aneurysms. A simple prognostic model utilizing only a maximum coronary artery z-score ≥2.5 at initial presentation was optimal to predict CAA during follow-up (area under the curve: 0.84; 95% CI: 0.80, 0.88).
CONCLUSION
From our Latin American population, coronary artery z-score ≥2.5 at initial presentation was the most important prognostic factor preceding CAA during follow-up. These results highlight the importance of early echocardiography during the initial presentation of KD.
Topics: Child; Humans; Coronary Aneurysm; Immunoglobulins, Intravenous; Latin America; Mucocutaneous Lymph Node Syndrome; Retrospective Studies
PubMed: 36775190
DOI: 10.1016/j.jpeds.2023.02.001 -
BioRxiv : the Preprint Server For... Jan 2023Bloom syndrome helicase (BLM) is a RecQ-family helicase implicated in a variety of cellular processes, including DNA replication, DNA repair, and telomere maintenance....
Bloom syndrome helicase (BLM) is a RecQ-family helicase implicated in a variety of cellular processes, including DNA replication, DNA repair, and telomere maintenance. Mutations in human cause Bloom syndrome (BS), an autosomal recessive disorder that leads to myriad negative health impacts including a predisposition to cancer. BS-causing mutations in often negatively impact BLM ATPase and helicase activity. While mutations that cause BS have been well characterized both and , there are other less studied mutations that exist in the human population that do not lead to BS. Two of these non-BS mutations, encoding BLM P868L and BLM G1120R, when homozygous, increase sister chromatid exchanges in human cells. To characterize these naturally occurring BLM mutant proteins , we purified the BLM catalytic core (BLM , residues 636-1298) with either the P868L or G1120R substitution. We also purified a BLM K869A K870A mutant protein, which alters a lysine-rich loop proximal to the P868 residue. We found that BLM P868L and G1120R proteins were both able to hydrolyze ATP, bind diverse DNA substrates, and unwind G-quadruplex and duplex DNA structures. Molecular dynamics simulations suggest that the P868L substitution weakens the DNA interaction with the winged-helix domain of BLM and alters the orientation of one lobe of the ATPase domain. Because BLM P868L and G1120R retain helicase function , it is likely that the increased genome instability is caused by specific impacts of the mutant proteins . Interestingly, we found that BLM K869A K870A has diminished ATPase activity, weakened binding to duplex DNA structures, and less robust helicase activity compared to wild-type BLM . Thus, the lysine-rich loop may have an important role in ATPase activity and specific binding and DNA unwinding functions in BLM.
PubMed: 36747637
DOI: 10.1101/2023.01.26.525669 -
Journal of Virological Methods Apr 2023The development of hematopoietic stem cell (HSCs) gene therapy for DNA repair disorders, such as Fanconi anemia and Bloom syndrome, is challenging because of the...
The development of hematopoietic stem cell (HSCs) gene therapy for DNA repair disorders, such as Fanconi anemia and Bloom syndrome, is challenging because of the induction of HSCs apoptosis by cytokine stimulation. Although the Baboon envelope pseudotyped lentiviral vector (BaEV-Rless-LV) has been reported as a non-stimulatory gene transfer tool, the virus titer of BaEV-Rless-LV is too low for use in clinical applications. Transfected 293 T cells with helper plasmids, including the BaEV-Rless plasmid, showed morphological changes, such as syncytium formation and detachment. To establish a novel protocol for producing a high titer of BaEV-Rless-LV, we optimized three aspects of a basic virus production protocol by focusing on modifying culture conditions and the use of reagents: the virus titer increased 3-fold when the amount of BaEV-Rless plasmid was increased 1.2-fold; the highest titer was obtained when the viral supernatant was harvested at 48-h post-transfection, despite complete syncytium formation and detachment of the 293 T cells; and the use of poly-L-lysine-coated culture plates to enhance the adhesion and proliferation of 293 T cells and prevent detachment doubled the titer. Collectively, our novel protocol resulted in a 10-fold titer increase compared to the basic protocol and may be useful in clinical applications for treating DNA repair disorders.
Topics: Animals; Lentivirus; Plasmids; Transfection; Hematopoietic Stem Cells; Papio; Giant Cells; Genetic Vectors; Transduction, Genetic
PubMed: 36739979
DOI: 10.1016/j.jviromet.2023.114689 -
Molecular Psychiatry Apr 2023Irritable bowel syndrome (IBS) is the most prevalent disorder of brain-gut interactions that affects between 5 and 10% of the general population worldwide. The current... (Review)
Review
Irritable bowel syndrome (IBS) is the most prevalent disorder of brain-gut interactions that affects between 5 and 10% of the general population worldwide. The current symptom criteria restrict the diagnosis to recurrent abdominal pain associated with altered bowel habits, but the majority of patients also report non-painful abdominal discomfort, associated psychiatric conditions (anxiety and depression), as well as other visceral and somatic pain-related symptoms. For decades, IBS was considered an intestinal motility disorder, and more recently a gut disorder. However, based on an extensive body of reported information about central, peripheral mechanisms and genetic factors involved in the pathophysiology of IBS symptoms, a comprehensive disease model of brain-gut-microbiome interactions has emerged, which can explain altered bowel habits, chronic abdominal pain, and psychiatric comorbidities. In this review, we will first describe novel insights into several key components of brain-gut microbiome interactions, starting with reported alterations in the gut connectome and enteric nervous system, and a list of distinct functional and structural brain signatures, and comparing them to the proposed brain alterations in anxiety disorders. We will then point out the emerging correlations between the brain networks with the genomic, gastrointestinal, immune, and gut microbiome-related parameters. We will incorporate this new information into a systems-based disease model of IBS. Finally, we will discuss the implications of such a model for the improved understanding of the disorder and the development of more effective treatment approaches in the future.
Topics: Humans; Irritable Bowel Syndrome; Enteric Nervous System; Abdominal Pain; Brain
PubMed: 36732586
DOI: 10.1038/s41380-023-01972-w -
Circulation Jan 2023Cardiovascular disease is a leading cause of morbidity and mortality in individuals with Down syndrome. Congenital heart disease is the most common cardiovascular... (Review)
Review
Cardiovascular disease is a leading cause of morbidity and mortality in individuals with Down syndrome. Congenital heart disease is the most common cardiovascular condition in this group, present in up to 50% of people with Down syndrome and contributing to poor outcomes. Additional factors contributing to cardiovascular outcomes include pulmonary hypertension; coexistent pulmonary, endocrine, and metabolic diseases; and risk factors for atherosclerotic disease. Moreover, disparities in the cardiovascular care of people with Down syndrome compared with the general population, which vary across different geographies and health care systems, further contribute to cardiovascular mortality; this issue is often overlooked by the wider medical community. This review focuses on the diagnosis, prevalence, and management of cardiovascular disease encountered in people with Down syndrome and summarizes available evidence in 10 key areas relating to Down syndrome and cardiac disease, from prenatal diagnosis to disparities in care in areas of differing resource availability. All specialists and nonspecialist clinicians providing care for people with Down syndrome should be aware of best clinical practice in all aspects of care of this distinct population.
Topics: Pregnancy; Female; Humans; Cardiovascular Diseases; Down Syndrome; Consensus; Cardiovascular System; Heart Defects, Congenital
PubMed: 36716257
DOI: 10.1161/CIRCULATIONAHA.122.059706