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Structural insights on TFIIH in transcription and DNA repair / Trevor van Eeuwen.
- Format:
- Book
- Thesis/Dissertation
- Author/Creator:
- Eeuwen, Trevor van, author.
- Language:
- English
- Subjects (All):
- Biochemistry.
- Biophysics.
- Mass spectrometry.
- RNA polymerase.
- Regulation.
- Phosphatase.
- DNA repair.
- Amino acids.
- Scientific imaging.
- Genomes.
- Phosphorylation.
- Yeast.
- Genes.
- Enzymes.
- Kinases.
- Radiation.
- Roles.
- Transcription factors.
- Proteins.
- Biochemistry and Molecular Biophysics--Penn dissertations.
- Penn dissertations--Biochemistry and Molecular Biophysics.
- Local Subjects:
- Biochemistry.
- Biophysics.
- Mass spectrometry.
- RNA polymerase.
- Regulation.
- Phosphatase.
- DNA repair.
- Amino acids.
- Scientific imaging.
- Genomes.
- Phosphorylation.
- Yeast.
- Genes.
- Enzymes.
- Kinases.
- Radiation.
- Roles.
- Transcription factors.
- Proteins.
- Biochemistry and Molecular Biophysics--Penn dissertations.
- Penn dissertations--Biochemistry and Molecular Biophysics.
- Genre:
- Academic theses.
- Physical Description:
- 1 online resource (141 pages)
- Contained In:
- Dissertations Abstracts International 83-03B.
- Place of Publication:
- [Philadelphia, Pennsylvania] : University of Pennsylvania ; Ann Arbor : ProQuest Dissertations & Theses, 2021.
- Language Note:
- English
- System Details:
- Mode of access: World Wide Web.
- text file
- Summary:
- TFIIH is an essential, ten protein complex that necessary in both transcription initiation and Nucleotide Excision Repair (NER). During transcription initiation, the general transcription factor TFIIH marks RNA polymerase II by phosphorylating Ser5 of the C-terminal domain (CTD) of Rpb1, which is followed by extensive modifications coupled to transcription elongation, mRNA processing, and histone dynamics. We have determined a 3.5 A resolution cryo-EM structure of the TFIIH kinase module (TFIIK in yeast), which is composed of Kin28, Ccl1, and Tfb3, yeast homologues of CDK7, Cyclin H, and MAT1, respectively. The C-terminal region of Tfb3 was lying at the edge of catalytic cleft of Kin28, where a conserved Tfb3 helix served to stabilize the activation loop in its active conformation. By combining the structure of TFIIK with previous cryo-EM structure of the pre-initiation complex, we extend the previously proposed model of the CTD path to the active site of TFIIK. The versatile NER pathway initiates as the XPC-RAD23B-CETN2 complex first recognizes DNA lesions from the genomic DNA and recruits the general transcription factor complex, TFIIH, for subsequent lesion verification. Here, we present a cryo-EM structure of an NER initiation complex containing Rad4-Rad23-Rad33 (yeast homologue ofXPC-RAD23B-CETN2) and 7-subunit core TFIIH assembled on a carcinogen-DNA adduct lesion at 3.9-9.2 A resolution. A ~30-bp DNA duplex could be mapped as it straddles between Rad4 and the Ssl2 (XPB) subunit of TFIIH on the 3' and 5' side of the lesion, respectively. The simultaneous binding with Rad4 and TFIIH was permitted by an unwinding of DNA at the lesion. Translocation coupled with torque generation by Ssl2 and Rad4 would extend the DNA unwinding at the lesion and deliver the damaged strand to Rad3 (XPD) in an open form suitable for subsequent lesion scanning and verification. These two structural studies have demonstrated some functional conservation in the mechanism of DNA unwinding between transcription and NER and provide the groundwork for further investigations into TFIIH function.
- Notes:
- Source: Dissertations Abstracts International, Volume: 83-03, Section: B.
- Includes supplementary digital materials.
- Advisors: Murakami, Kenji; Committee members: Black, Ben E.; Van Duyne, Gregory D.; Busino, Luca; Min, Jung-Hyun.
- Department: Biochemistry and Molecular Biophysics.
- Ph.D. University of Pennsylvania 2021.
- Local Notes:
- School code: 0175
- ISBN:
- 9798535589848
- Access Restriction:
- Restricted for use by site license.
- This item must not be sold to any third party vendors.
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