CD63 regulated Lysosomal degradation of ExtranucleAR DNA during AGing
Description: During aging, accumulation of senescent cells results in the gradual deterioration of tissue homeostasis. Senescent cells are characterized by compromised DNA and nuclear envelope integrity, which they fail to resolve due to dysfunctional lysosomes. Yet, mechanisms that enforce lysosomal clearance of damaged nuclear DNA in youth, and how they become dysfunctional and cause senescence during aging are not known. Our new results reveal that the tetraspanin CD63 defines a novel axis of damaged DNA clearance by lysosomes that is upregulated during aging of macrophages. We find that nuclear envelope rupture causes DNA damage, leading to senescence and acquisition of CD63+ endolysosomes that are required to clear DNA. We associate these effects to novel functions of CD63 in lysosomal DNAse trafficking and maturation of autophagolysosomes. The main objective of “CLEAR-DNAge” is to establish how the CD63-dependent axis clears damaged DNA into lysosomes, and how this becomes dysregulated in senescence. We will combine imaging and biochemistry approaches in mouse strains, derived primary cells and cell lines to investigate the mechanisms and signaling pathways regulating induction of the CD63+ autolysosome upon accumulation of DNA damage. We will study the role of CD63 during generation of nucleophagolysosomes and lysosomal DNA degradation at subcellular scale. We will live-track intercellular transfer of exosomes associated to DNA during aging in vivo to reveal their role in paracrine senescence transmission. This project will thus lead to a better understanding of the mechanisms linking nuclear envelope damage, DNA damage and lysosomal function that support cellular senescence. To realize this innovative project, we have currently an international competitive advantage thanks to our preliminary results and respective expertise in CD63 and exosomes/lysosome biology and in extranuclear DNA sensing following nuclear envelope rupture and senescence.
Funder: Agence Nationale de la Recherche
Amount: €528,300
Funding type: research
Funder scheme: AAPG2024
Start date: 2024-11-01
Investigator: Nicolas MANEL
Institution: Institut Curie Paris
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Funded outputs count: 2
Funder award ID: ANR-24-CE14-4284
OpenAlex ID: G281765290