In response to DNA double-strand breaks (DSBs), chromatin modifications orchestrate DNA repair pathways thus safeguarding genome integrity. Recent studies have uncovered a key role for heterochromatin marks and associated factors in shaping DSB repair within the nucleus. In this review, we present our current knowledge of the interplay between heterochromatin marks and DSB repair. We discuss the impact of heterochromatin features, either pre-existing in heterochromatin domains or established in euchromatin, on DSB repair pathway choice. We emphasize how heterochromatin decompaction and mobility further support DSB repair, focusing on recent mechanistic insights into these processes. Finally, we speculate about potential molecular players involved in the maintenance or the erasure of heterochromatin marks following DSB repair, and their implications for restoring epigenome function and integrity.
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http://dx.doi.org/10.3389/fgene.2021.730696 | DOI Listing |
Heliyon
January 2025
Instituto de Bioingeniería, Universidad Miguel Hernández, Campus de Elche, 03202, Elche, Spain.
The human deoxyribonucleoside triphosphatase (dNTPase) Sterile alpha motif and histidine-aspartate domain containing protein 1 (SAMHD1) has a dNTPase-independent role in repairing DNA double-strand breaks (DSBs) by homologous recombination (HR). Here, we show that VENOSA4 (VEN4), the probable ortholog of SAMHD1, also functions in DSB repair by HR. The loss-of-function mutants showed increased DNA ploidy and deregulated DNA repair genes, suggesting DNA damage accumulation.
View Article and Find Full Text PDFCytokine Growth Factor Rev
January 2025
Center for Precision Medicine, China Medical University Hospital, China Medical University, Taichung, Taiwan; Department of Pathology, College of Medicine, China Medical University, Taichung, Taiwan. Electronic address:
Receptor tyrosine kinases (RTKs) are membrane sensors that monitor alterations in the extracellular milieu and translate this information into appropriate cellular responses. Epidermal growth factor receptor (EGFR) is the most well-known model in which gene expression is upregulated by mitogenic signals through the activation of multiple signaling cascades or by nuclear translocation of the full-length EGFR protein. RON (Receptuer d'Origine Nantatise, also known as macrophage stimulating 1 receptor, MST1R) has recently gained attention as a therapeutic target for human cancer.
View Article and Find Full Text PDFGenetics
January 2025
Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Bloom Syndrome helicase (Blm) is a RecQ family helicase involved in DNA repair, cell-cycle progression, and development. Pathogenic variants in human BLM cause the autosomal recessive disorder Bloom Syndrome, characterized by predisposition to numerous types of cancer. Prior studies of Drosophila Blm mutants lacking helicase activity or protein have shown sensitivity to DNA damaging agents, defects in repairing DNA double-strand breaks (DSBs), female sterility, and improper segregation of chromosomes in meiosis.
View Article and Find Full Text PDFbioRxiv
December 2024
Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 North Wolfe Street, CMSC 5 South, Baltimore, MD21287.
Huntington's Disease (HD), a progressive neurodegenerative disorder with no disease-modifying therapies, is caused by a CAG repeat expansion in the HD gene encoding polyglutamine-expanded huntingtin (HTT) protein. Mechanisms of HD cellular pathogenesis and cellular functions of the normal and mutant HTT proteins are still not completely understood. HTT protein has numerous interaction partners, and it likely provides a scaffold for assembly of multiprotein complexes many of which may be altered in HD.
View Article and Find Full Text PDFNat Commun
January 2025
Crick-GSK Biomedical LinkLabs, GSK, Gunnels Wood Road, Stevenage, Hertfordshire, UK.
Identifying pharmacological probes for human proteins represents a key opportunity to accelerate the discovery of new therapeutics. High-content screening approaches to expand the ligandable proteome offer the potential to expedite the discovery of novel chemical probes to study protein function. Screening libraries of reactive fragments by chemoproteomics offers a compelling approach to ligand discovery, however, optimising sample throughput, proteomic depth, and data reproducibility remains a key challenge.
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