Envisioning how the prototypic molecular machine TFIIH functions in transcription initiation and DNA repair
| Autor: | Chi Lin Tsai, Ivaylo Ivanov, Orlando D. Schärer, Amer Bralic, Chunli Yan, Samir M. Hamdan, Susan E. Tsutakawa, John A. Tainer, Walter J. Chazin |
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| Rok vydání: | 2020 |
| Předmět: |
Models
Molecular DNA Repair Protein Conformation Biochemistry 0302 clinical medicine Transcription (biology) Models 2.1 Biological and endogenous factors Aetiology Transcription Initiation Genetic Cancer 0303 health sciences biology TFIIH Transcription initiation DNA-Binding Proteins Transcription-coupled repair 030220 oncology & carcinogenesis Transcription factor II H DNA damage DNA repair XPB 1.1 Normal biological development and functioning XPD Computational biology Article Helicase 03 medical and health sciences Genetic Underpinning research Genetics Humans Molecular Biology 030304 developmental biology Xeroderma Pigmentosum Group D Protein DNA replication DNA Helicases Molecular Cell Biology DNA Human genetics Nucleotide excision repair Good Health and Well Being Translocase biology.protein Generic health relevance Biochemistry and Cell Biology Transcription Factor TFIIH DNA Damage Developmental Biology |
| Zdroj: | DNA Repair (Amst) |
| Popis: | Critical for transcription initiation and bulky lesion DNA repair, TFIIH provides an exemplary system to connect molecular mechanisms to biological outcomes due to its strong genetic links to different specific human diseases. Recent advances in structural and computational biology provide a unique opportunity to re-examine biologically relevant molecular structures and develop possible mechanistic insights for the large dynamic TFIIH complex. TFIIH presents many puzzles involving how its two SF2 helicase family enzymes, XPB and XPD, function in transcription initiation and repair: how do they initiate transcription, detect and verify DNA damage, select the damaged strand for incision, coordinate repair with transcription and cell cycle through Cdk-activating-kinase (CAK) signaling, and result in very different specific human diseases associated with cancer, aging, and development from single missense mutations? By joining analyses of breakthrough cryo-electron microscopy (cryo-EM) structures and advanced computation with data from biochemistry and human genetics, we develop unified concepts and molecular level understanding for TFIIH functions with a focus on structural mechanisms. We provocatively consider that TFIIH may have first evolved from evolutionary pressure for TCR to resolve arrested transcription blocks to DNA replication and later added its key roles in transcription initiation and global DNA repair. We anticipate that this level of mechanistic information will have significant impact on thinking about TFIIH, laying a robust foundation suitable to develop new paradigms for DNA transcription initiation and repair along with insights into disease prevention, susceptibility, diagnosis and interventions. |
| Databáze: | OpenAIRE |
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