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1.
Nat Commun ; 15(1): 3490, 2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38664429

RESUMO

Congenital nucleotide excision repair (NER) deficiency gives rise to several cancer-prone and/or progeroid disorders. It is not understood how defects in the same DNA repair pathway cause different disease features and severity. Here, we show that the absence of functional ERCC1-XPF or XPG endonucleases leads to stable and prolonged binding of the transcription/DNA repair factor TFIIH to DNA damage, which correlates with disease severity and induces senescence features in human cells. In vivo, in C. elegans, this prolonged TFIIH binding to non-excised DNA damage causes developmental arrest and neuronal dysfunction, in a manner dependent on transcription-coupled NER. NER factors XPA and TTDA both promote stable TFIIH DNA binding and their depletion therefore suppresses these severe phenotypical consequences. These results identify stalled NER intermediates as pathogenic to cell functionality and organismal development, which can in part explain why mutations in XPF or XPG cause different disease features than mutations in XPA or TTDA.


Assuntos
Caenorhabditis elegans , Dano ao DNA , Reparo do DNA , Proteínas de Ligação a DNA , Endonucleases , Fator de Transcrição TFIIH , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/genética , Humanos , Animais , Fator de Transcrição TFIIH/metabolismo , Fator de Transcrição TFIIH/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Endonucleases/metabolismo , Endonucleases/genética , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteína de Xeroderma Pigmentoso Grupo A/metabolismo , Proteína de Xeroderma Pigmentoso Grupo A/genética , Ligação Proteica , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Mutação , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética
2.
Nat Commun ; 15(1): 6374, 2024 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-39075067

RESUMO

Transcription-blocking DNA lesions are specifically targeted by transcription-coupled nucleotide excision repair (TC-NER), which removes a broad spectrum of DNA lesions to preserve transcriptional output and thereby cellular homeostasis to counteract aging. TC-NER is initiated by the stalling of RNA polymerase II at DNA lesions, which triggers the assembly of the TC-NER-specific proteins CSA, CSB and UVSSA. CSA, a WD40-repeat containing protein, is the substrate receptor subunit of a cullin-RING ubiquitin ligase complex composed of DDB1, CUL4A/B and RBX1 (CRL4CSA). Although ubiquitination of several TC-NER proteins by CRL4CSA has been reported, it is still unknown how this complex is regulated. To unravel the dynamic molecular interactions and the regulation of this complex, we apply a single-step protein-complex isolation coupled to mass spectrometry analysis and identified DDA1 as a CSA interacting protein. Cryo-EM analysis shows that DDA1 is an integral component of the CRL4CSA complex. Functional analysis reveals that DDA1 coordinates ubiquitination dynamics during TC-NER and is required for efficient turnover and progression of this process.


Assuntos
Proteínas de Ligação a DNA , Reparo por Excisão , Ubiquitina-Proteína Ligases , Humanos , Microscopia Crioeletrônica , Proteínas Culina/metabolismo , Proteínas Culina/genética , Dano ao DNA , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Células HEK293 , Ligação Proteica , Receptores de Interleucina-17 , Transcrição Gênica , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitinação
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