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Related Concept Videos

Nucleosome Remodeling02:54

Nucleosome Remodeling

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Nucleosomes are the basic units of chromatin compaction. Each nucleosome consists of the DNA bound tightly around a histone core, which makes the DNA inaccessible to DNA binding proteins such as DNA polymerase and RNA polymerase. Hence, the fundamental problem is to ensure access to DNA when appropriate, despite the compact and protective chromatin structure.
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Cardiomyopathy IV: Restrictive Cardiomyopathy01:29

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Restrictive cardiomyopathy (RCM) is a rare heart muscle disease characterized by impaired ventricular filling due to stiffened ventricular walls, leading to significant diastolic dysfunction.EtiologyRestrictive cardiomyopathy can arise from both inherited and acquired diseases, many of which are systemic. It is categorized into four main types: infiltrative, storage, non-infiltrative, and endomyocardial diseases.Infiltrative diseases, such as amyloidosis, lead to RCM by depositing amyloid...
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Cardiomyopathy III: Hypertrophic Cardiomyopathy01:29

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Hypertrophic cardiomyopathy, or HCM, is an autosomal dominant genetic disorder characterized by asymmetric left ventricular hypertrophy without ventricular dilation. It is more common in men and is typically diagnosed in young, athletic adults.EtiologyHCM is primarily genetic and is caused by mutations in genes encoding sarcomeric proteins. Researchers have identified over 1400 mutations across at least 11 different genes. Among these, the most frequently occurring mutations are found in the...
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Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
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DNA replication is initiated at sites containing predefined DNA sequences known as origins of replication. DNA is unwound at these sites by the minichromosome maintenance (MCM) helicase and other factors such as Cdc45 and the associated GINS complex.The unwound single strands are protected by replication protein A (RPA) until DNA polymerase starts synthesizing DNA at the 5’ end of the strand in the same direction as the replication fork. To prevent the replication fork from falling apart,...
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An organism’s genome needs to be duplicated in an efficient and error-free manner for its growth and survival. The replication fork is a Y-shaped active region where two strands of DNA are separated and replicated continuously. The coupling of DNA unzipping and complementary strand synthesis is a characteristic feature of a replication fork.   Organisms with small circular DNA, such as E. coli, often have a single origin of replication; therefore, they have only two replication...
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Related Experiment Video

Updated: Oct 26, 2025

Sarcomere Shortening of Pluripotent Stem Cell-Derived Cardiomyocytes using Fluorescent-Tagged Sarcomere Proteins.
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Replication Stress Response Modifies Sarcomeric Cardiomyopathy Remodeling.

Soumojit Pal1, Benjamin R Nixon1, Michael S Glennon1

  • 1Division of Cardiology Department of Medicine Heart, Lung Blood and Vascular Medicine InstituteSchool of MedicineUniversity of PittsburghUniversity of Pittsburgh Medical Center PA.

Journal of the American Heart Association
|July 29, 2021
PubMed
Summary
This summary is machine-generated.

Sarcomere gene mutations cause DNA damage and replication stress in heart cells, leading to cardiomyopathy. Targeting this stress response may reduce pathological heart remodeling in these conditions.

Keywords:
DNA damageataxia telangiectasia and rad3 relatedcardiac myosin‐binding protein 3cardiac troponin T2cardiomyocyte hypertrophyendoreplicationhypertrophic cardiomyopathy

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Area of Science:

  • Cardiovascular Biology
  • Molecular Cardiology
  • Genetics

Background:

  • Sarcomere gene mutations are known to cause cardiomyocyte hypertrophy and pathological myocardial remodeling.
  • Phenotypic heterogeneity suggests the involvement of regulatory modifiers in sarcomeric cardiomyopathies.
  • This study investigates the role of cardiomyocyte genotoxic stress as a modifier of pathological ventricular remodeling.

Purpose of the Study:

  • To investigate the hypothesis that sarcomere dysfunction induces cardiomyocyte genotoxic stress, thereby modifying pathological ventricular remodeling.
  • To explore the underlying mechanisms linking sarcomere mutations to cardiac pathology.

Main Methods:

  • Utilized a Mybpc3-deficient murine model (Mybpc3-/-) to study early-stage cardiomyopathy.
  • Assessed cardiomyocyte nuclear DNA damage, ataxia telangiectasia and rad3-related (ATR) phosphorylation, and p53 protein.
  • Investigated the impact of inhibiting ATR or deleting p53 on cardiac remodeling and hypertrophy.
  • Examined replication stress response activation and cardiomyocyte aneuploidy in human and murine models with various sarcomere gene mutations.

Main Results:

  • A surge in cardiomyocyte nuclear DNA damage and activation of the DNA damage response (ATR phosphorylation, p53 accumulation) was observed in Mybpc3-/- mice during early cardiomyopathy.
  • Dysregulated cardiomyocyte DNA synthesis, leading to replication stress, was identified as the cause of DNA damage.
  • Selective inhibition of ATR or cardiomyocyte deletion of p53 attenuated pathological left ventricular remodeling and cardiomyocyte hypertrophy in Mybpc3-/- animals.
  • Replication stress response activation and cardiomyocyte aneuploidy were evident in human and murine models with diverse sarcomere gene mutations.

Conclusions:

  • Sarcomere mutations activate the cardiomyocyte replication stress response.
  • This replication stress response significantly modifies pathological myocardial remodeling in sarcomeric cardiomyopathy.
  • The findings highlight replication stress as a potential therapeutic target for sarcomeric cardiomyopathies.