ABSTRACT
The accumulation of irreparable cellular damage restricts healthspan after acute stress or natural aging. Senescent cells are thought to impair tissue function, and their genetic clearance can delay features of aging. Identifying how senescent cells avoid apoptosis allows for the prospective design of anti-senescence compounds to address whether homeostasis can also be restored. Here, we identify FOXO4 as a pivot in senescent cell viability. We designed a FOXO4 peptide that perturbs the FOXO4 interaction with p53. In senescent cells, this selectively causes p53 nuclear exclusion and cell-intrinsic apoptosis. Under conditions where it was well tolerated in vivo, this FOXO4 peptide neutralized doxorubicin-induced chemotoxicity. Moreover, it restored fitness, fur density, and renal function in both fast aging XpdTTD/TTD and naturally aged mice. Thus, therapeutic targeting of senescent cells is feasible under conditions where loss of health has already occurred, and in doing so tissue homeostasis can effectively be restored.
Subject(s)
Aging/pathology , Antibiotics, Antineoplastic/adverse effects , Cell-Penetrating Peptides/pharmacology , Doxorubicin/adverse effects , Aging/drug effects , Animals , Antibiotics, Antineoplastic/administration & dosage , Antibiotics, Antineoplastic/pharmacology , Apoptosis , Cell Cycle Proteins , Cell Line , Cell Survival , Cellular Senescence/drug effects , Doxorubicin/administration & dosage , Doxorubicin/pharmacology , Female , Fibroblasts/cytology , Forkhead Transcription Factors/chemistry , Forkhead Transcription Factors/metabolism , Humans , Inclusion Bodies/drug effects , Inclusion Bodies/metabolism , Inclusion Bodies/pathology , Kidney/drug effects , Kidney/physiology , Liver/drug effects , Liver/physiology , Male , Mice , Trichothiodystrophy Syndromes/drug therapy , Tumor Suppressor Protein p53/metabolismABSTRACT
Transcription factor IIH (TFIIH) is a multiprotein complex involved in both transcription and DNA repair, revealing a striking functional link between these two processes. Some of its subunits also belong to complexes involved in other cellular processes, such as chromosome segregation and cell cycle regulation, emphasizing the multitasking capabilities of this factor. This review aims to depict the structure of TFIIH and to dissect the roles of its subunits in different cellular mechanisms. Our understanding of the biochemistry of TFIIH has greatly benefited from studies focused on diseases related to TFIIH mutations. We address the etiology of these disorders and underline the fact that TFIIH can be considered a promising target for therapeutic strategies.
Subject(s)
DNA Repair/drug effects , Transcription Factor TFIIH/genetics , Transcription, Genetic/drug effects , Trichothiodystrophy Syndromes/genetics , Xeroderma Pigmentosum/genetics , Cell Cycle/drug effects , Cell Cycle/genetics , Cell Cycle Proteins/antagonists & inhibitors , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Chromosome Segregation , DNA/genetics , DNA/metabolism , DNA Damage , Humans , Models, Molecular , Molecular Targeted Therapy , Mutation , Phenylenediamines/therapeutic use , Protein Subunits/antagonists & inhibitors , Protein Subunits/genetics , Protein Subunits/metabolism , Pyrimidines/therapeutic use , Spironolactone/therapeutic use , Transcription Factor TFIIH/antagonists & inhibitors , Transcription Factor TFIIH/metabolism , Trichothiodystrophy Syndromes/drug therapy , Trichothiodystrophy Syndromes/metabolism , Trichothiodystrophy Syndromes/pathology , Xeroderma Pigmentosum/drug therapy , Xeroderma Pigmentosum/metabolism , Xeroderma Pigmentosum/pathologySubject(s)
Erythema/pathology , Immunization, Passive/adverse effects , Skin/pathology , Adolescent , Agammaglobulinemia/drug therapy , Child , Common Variable Immunodeficiency/drug therapy , Erythema/immunology , Female , Humans , Immunoglobulin G/administration & dosage , Immunoglobulin G/therapeutic use , Injections, Subcutaneous , Male , Necrosis , Staphylococcus aureus/drug effects , Staphylococcus aureus/isolation & purification , Trichothiodystrophy Syndromes/drug therapyABSTRACT
OBJECTIVE: Evaluation of results in a consecutive series of 76 prenatal diagnoses for xeroderma pigmentosum (XP) and trichothiodystrophy (TTD) made since 1977. METHODS: UV-induced DNA repair synthesis was assessed by the autoradiographic measurement of the incorporation of (3)H-thymidine. RESULTS: XP was diagnosed in 19 of the 76 investigated pregnancies at risk; cultured chorionic villus (CV) cells were used in 33 pregnancies with ten affected fetuses and cultured amniocytes in 43 pregnancies with nine affected fetuses. In four cases, CVS results were corroborated by subsequent investigation of amniocytes because maternal cell contamination in the CV cell culture was either present or could not be excluded. Uncertain results in two other cases with intermediate DNA repair capacity and severe maternal cell contamination required further investigation. Median time needed for cell culture and analysis was 25 days. To reduce intra-assay variations, a modification of the DNA repair synthesis assay has recently been developed. In this assay, patients and controls are investigated simultaneously in mixed cultures of cells labelled with polystyrene beads. CONCLUSION: Reliable prenatal diagnosis for XP and TTD can be made by the demonstration of clearly reduced UV-induced DNA repair synthesis due to defective global genome nucleotide excision repair.
