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1.
Sci Adv ; 7(47): eabj5769, 2021 11 19.
Article in English | MEDLINE | ID: mdl-34797720

ABSTRACT

How DNA damage leads to chronic inflammation and tissue degeneration with aging remains to be fully resolved. Here, we show that DNA damage leads to cellular senescence, fibrosis, loss-of-tissue architecture, and chronic pancreatitis in mice with an inborn defect in the excision repair cross complementation group 1 (Ercc1) gene. We find that DNA damage-driven R-loops causally contribute to the active release and buildup of single-stranded DNAs (ssDNAs) in the cytoplasm of cells triggering a viral-like immune response in progeroid and naturally aged pancreata. To reduce the proinflammatory load, we developed an extracellular vesicle (EV)-based strategy to deliver recombinant S1 or ribonuclease H nucleases in inflamed Ercc1−/− pancreatic cells. Treatment of Ercc1−/− animals with the EV-delivered nuclease cargo eliminates DNA damage-induced R-loops and cytoplasmic ssDNAs alleviating chronic inflammation. Thus, DNA damage-driven ssDNAs causally contribute to tissue degeneration, Ercc1−/− paving the way for novel rationalized intervention strategies against age-related chronic inflammation.


Subject(s)
DNA Repair , R-Loop Structures , Animals , Cytoplasm , DNA Damage , DNA, Single-Stranded , DNA-Binding Proteins/genetics , Endonucleases/genetics , Inflammation , Mice
2.
Trends Genet ; 36(10): 777-791, 2020 10.
Article in English | MEDLINE | ID: mdl-32684438

ABSTRACT

Nuclear DNA damage contributes to cellular malfunction and the premature onset of age-related diseases, including cancer. Until recently, the canonical DNA damage response (DDR) was thought to represent a collection of nuclear processes that detect, signal and repair damaged DNA. However, recent evidence suggests that beyond nuclear events, the DDR rewires an intricate network of metabolic circuits, fine-tunes protein synthesis, trafficking, and secretion as well as balances growth with defense strategies in response to genotoxic insults. In this review, we discuss how the active DDR signaling mobilizes extranuclear and systemic responses to promote cellular homeostasis and organismal survival in health and disease.


Subject(s)
Aging , Cellular Reprogramming , Cellular Senescence , DNA Damage , DNA Repair Enzymes/metabolism , DNA Repair , Neoplasms/genetics , Animals , DNA Repair Enzymes/genetics , Humans , Mutation
3.
Mech Ageing Dev ; 165(Pt A): 17-26, 2017 07.
Article in English | MEDLINE | ID: mdl-27702596

ABSTRACT

Nuclear architecture and the chromatin state affect most-if not all- DNA-dependent transactions, including the ability of cells to sense DNA lesions and restore damaged DNA back to its native form. Recent evidence points to functional links between DNA damage sensors, DNA repair mechanisms and the innate immune responses. The latter raises the question of how such seemingly disparate processes operate within the intrinsically complex nuclear landscape and the chromatin environment. Here, we discuss how DNA damage-induced immune responses operate within chromatin and the distinct sub-nuclear compartments highlighting their relevance to chronic inflammation.


Subject(s)
Chromatin/immunology , DNA Damage/immunology , DNA Repair/immunology , Immunity, Innate , Animals , Chromatin/genetics , DNA Repair/genetics , Humans , Inflammation/genetics , Inflammation/immunology , Inflammation/pathology
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