Envisioning how the prototypic molecular machine TFIIH functions in transcription initiation and DNA repair

Susan E. Tsutakawa, Chi-Lin Tsai, Chunli Yan, Amer Bralic, Walter J. Chazin, Samir Hamdan, Orlando D. Schärer, Ivaylo Ivanov, John A. Tainer

Research output: Contribution to journalArticlepeer-review

30 Scopus citations


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 Cdkactivating-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.
Original languageEnglish (US)
Pages (from-to)102972
JournalDNA Repair
StatePublished - Sep 17 2020

Bibliographical note

KAUST Repository Item: Exported on 2020-10-04
Acknowledged KAUST grant number(s): CRG3
Acknowledgements: We thank the researchers, patients, and families who have critically contributed to defining the genetic basis for TFIIH pathophysiology.
Work on TFIIH is supported by NCI P01 CA092584 (to S.E.T., O.D.S, W. J.C., I.I., J.A.T.), R01 CA218315 (to O.D.S., W.J.C.), NCI R35 CA220430
(to J.A.T.); NIGMS R01GM110387 (to S.E.T. and I.I.); and KAUST CRG3 (to S.M.H and J.A.T.). J.A.T. is a CPRIT Scholar in Cancer Research and
acknowledges support by a Robert A. Welch Chemistry Chair. The O.D.S. laboratory is supported by the Korean Institute of Basic Science IBSR022-A1. I.I. acknowledges computational resources for TFIIH analysis provided by the NSF XSEDE programCHE110042 and the ORNL INCITE program under DOEDE-AC05-00OR22725.


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