In TFIIH the Arch domain of XPD is mechanistically essential for transcription and DNA repair

Peissert, S.; Sauer, Florian; Grabarczyk, Daniel B.; Braun, Cathy; Sander, Gudrun; Poterszman, Arnaud; Egly, Jean‐Marc; Kuper, Jochen; Kisker, Caroline

doi:10.1038/s41467-020-15241-9

Cited by 38 publications

(39 citation statements)

References 44 publications

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“…1 E ), the three ATP-consuming, functional centers of the complex. MAT1 forms interactions with regulatory elements on both CDK7 (see below) and XPD ( 28 , 32 , 34 ), highlighting its central regulatory role.…”

Section: Resultsmentioning

confidence: 99%

The cryoelectron microscopy structure of the human CDK-activating kinase

Greber

Perez-Bertoldi

Lim

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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The human CDK-activating kinase (CAK), a complex composed of cyclin-dependent kinase (CDK) 7, cyclin H, and MAT1, is a critical regulator of transcription initiation and the cell cycle. It acts by phosphorylating the C-terminal heptapeptide repeat domain of the RNA polymerase II (Pol II) subunit RPB1, which is an important regulatory event in transcription initiation by Pol II, and it phosphorylates the regulatory T-loop of CDKs that control cell cycle progression. Here, we have determined the three-dimensional (3D) structure of the catalytic module of human CAK, revealing the structural basis of its assembly and providing insight into CDK7 activation in this context. The unique third component of the complex, MAT1, substantially extends the interaction interface between CDK7 and cyclin H, explaining its role as a CAK assembly factor, and it forms interactions with the CDK7 T-loop, which may contribute to enhancing CAK activity. We have also determined the structure of the CAK in complex with the covalently bound inhibitor THZ1 in order to provide insight into the binding of inhibitors at the CDK7 active site and to aid in the rational design of therapeutic compounds.

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Section: Resultsmentioning

confidence: 99%

The cryoelectron microscopy structure of the human CDK-activating kinase

Greber

Perez-Bertoldi

Lim

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…In addition to the HD1 and 2 domains, hydra XPD has two other auxiliary domains – Fe-S domain and arch domain – within HD1 ( Figure 7B ). Similar to XPDs from other organisms ( Liu et al, 2008 ), hydra XPD Fe-S domain contains four key conserved cysteine residues while the arch domain contains basic amino acids arginine and lysine which are essential for its interactions with the other components of TFIIH ( Galande et al, 2018 ; Peissert et al, 2020 ; Figure 7B ). Hydra XPB and XPD thus seem to have all the domains essential for their function and share close similarities with respective homologs from other animals.…”

Section: Ner Pathway Genes In Hydramentioning

confidence: 96%

DNA Repair Repertoire of the Enigmatic Hydra

2021

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Since its discovery by Abraham Trembley in 1744, hydra has been a popular research organism. Features like spectacular regeneration capacity, peculiar tissue dynamics, continuous pattern formation, unique evolutionary position, and an apparent lack of organismal senescence make hydra an intriguing animal to study. While a large body of work has taken place, particularly in the domain of evolutionary developmental biology of hydra, in recent years, the focus has shifted to molecular mechanisms underlying various phenomena. DNA repair is a fundamental cellular process that helps to maintain integrity of the genome through multiple repair pathways found across taxa, from archaea to higher animals. DNA repair capacity and senescence are known to be closely associated, with mutations in several repair pathways leading to premature ageing phenotypes. Analysis of DNA repair in an animal like hydra could offer clues into several aspects including hydra’s purported lack of organismal ageing, evolution of DNA repair systems in metazoa, and alternative functions of repair proteins. We review here the different DNA repair mechanisms known so far in hydra. Hydra genes from various DNA repair pathways show very high similarity with their vertebrate orthologues, indicating conservation at the level of sequence, structure, and function. Notably, most hydra repair genes are more similar to deuterostome counterparts than to common model invertebrates, hinting at ancient evolutionary origins of repair pathways and further highlighting the relevance of organisms like hydra as model systems. It appears that hydra has the full repertoire of DNA repair pathways, which are employed in stress as well as normal physiological conditions and may have a link with its observed lack of senescence. The close correspondence of hydra repair genes with higher vertebrates further demonstrates the need for deeper studies of various repair components, their interconnections, and functions in this early metazoan.

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“…The motifs are located across two RecA helicase domains (Supplementary Figure 5). The first helicase domain also harbors two insertions, an iron sulfur cluster domain, and an arch domain, which are both important for duplex strand splitting (Ren et al, 2009;Peissert et al, 2020).…”

Section: Type Iv-a Systems Are Defense Systems With An Unknown Mechanism Of Action Involving a Ding Helicasementioning

confidence: 99%

Positioning Diverse Type IV Structures and Functions Within Class 1 CRISPR-Cas Systems

et al. 2021

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Type IV CRISPR systems encode CRISPR associated (Cas)-like proteins that combine with small RNAs to form multi-subunit ribonucleoprotein complexes. However, the lack of Cas nucleases, integrases, and other genetic features commonly observed in most CRISPR systems has made it difficult to predict type IV mechanisms of action and biological function. Here we summarize recent bioinformatic and experimental advancements that collectively provide the first glimpses into the function of specific type IV subtypes. We also provide a bioinformatic and structural analysis of type IV-specific proteins within the context of multi-subunit (class 1) CRISPR systems, informing future studies aimed at elucidating the function of these cryptic systems.

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In TFIIH the Arch domain of XPD is mechanistically essential for transcription and DNA repair

Cited by 38 publications

References 44 publications

The cryoelectron microscopy structure of the human CDK-activating kinase

The cryoelectron microscopy structure of the human CDK-activating kinase

DNA Repair Repertoire of the Enigmatic Hydra

Positioning Diverse Type IV Structures and Functions Within Class 1 CRISPR-Cas Systems

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