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Extended DNA threading through a dual-engine motor module of the activating signal co-integrator 1 complex.

ABSTRACT: Activating signal co-integrator 1 complex (ASCC) subunit 3 (ASCC3) supports diverse genome maintenance and gene expression processes, and contains tandem Ski2-like NTPase/helicase cassettes crucial for these functions. Presently, the molecular mechanisms underlying ASCC3 helicase activity and regulation remain unresolved. We present cryogenic electron microscopy, DNA-protein cross-linking/mass spectrometry as well as in vitro and cellular functional analyses of the ASCC3-TRIP4 sub-module of ASCC. Unlike the related spliceosomal SNRNP200 RNA helicase, ASCC3 can thread substrates through both helicase cassettes. TRIP4 docks on ASCC3 via a zinc finger domain and stimulates the helicase by positioning an ASC-1 homology domain next to the C-terminal helicase cassette of ASCC3, likely supporting substrate engagement and assisting the DNA exit. TRIP4 binds ASCC3 mutually exclusively with the DNA/RNA dealkylase, ALKBH3, directing ASCC3 for specific processes. Our findings define ASCC3-TRIP4 as a tunable motor module of ASCC that encompasses two cooperating NTPase/helicase units functionally expanded by TRIP4.

SUBMITTER: Jia J

PROVIDER: S-EPMC10076317 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Extended DNA threading through a dual-engine motor module of the activating signal co-integrator 1 complex.

Jia Junqiao J Hilal Tarek T Bohnsack Katherine E KE Chernev Aleksandar A Tsao Ning N Bethmann Juliane J Arumugam Aruna A Parmely Lane L Holton Nicole N Loll Bernhard B Mosammaparast Nima N Bohnsack Markus T MT Urlaub Henning H Wahl Markus C MC

Nature communications 20230405 1

Activating signal co-integrator 1 complex (ASCC) subunit 3 (ASCC3) supports diverse genome maintenance and gene expression processes, and contains tandem Ski2-like NTPase/helicase cassettes crucial for these functions. Presently, the molecular mechanisms underlying ASCC3 helicase activity and regulation remain unresolved. We present cryogenic electron microscopy, DNA-protein cross-linking/mass spectrometry as well as in vitro and cellular functional analyses of the ASCC3-TRIP4 sub-module of ASCC ...[more]

PMID: 37019967

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Project description:BackgroundWhole genome duplication (WGD) is a special case of gene duplication, observed rarely in animals, whereby all genes duplicate simultaneously through polyploidisation. Two rounds of WGD (2R-WGD) occurred at the base of vertebrates, giving rise to an enormous wave of genetic novelty, but a systematic analysis of functional consequences of this event has not yet been performed.ResultsWe show that 2R-WGD affected an overwhelming majority (74%) of signalling genes, in particular developmental pathways involving receptor tyrosine kinases, Wnt and transforming growth factor-β ligands, G protein-coupled receptors and the apoptosis pathway. 2R-retained genes, in contrast to tandem duplicates, were enriched in protein interaction domains and multifunctional signalling modules of Ras and mitogen-activated protein kinase cascades. 2R-WGD had a fundamental impact on the cell-cycle machinery, redefined molecular building blocks of the neuronal synapse, and was formative for vertebrate brains. We investigated 2R-associated nodes in the context of the human signalling network, as well as in an inferred ancestral pre-2R (AP2R) network, and found that hubs (particularly involving negative regulation) were preferentially retained, with high connectivity driving retention. Finally, microarrays and proteomics demonstrated a trend for gradual paralog expression divergence independent of the duplication mechanism, but inferred ancestral expression states suggested preferential subfunctionalisation among 2R-ohnologs (2ROs).ConclusionsThe 2R event left an indelible imprint on vertebrate signalling and the cell cycle. We show that 2R-WGD preferentially retained genes are associated with higher organismal complexity (for example, locomotion, nervous system, morphogenesis), while genes associated with basic cellular functions (for example, translation, replication, splicing, recombination; with the notable exception of cell cycle) tended to be excluded. 2R-WGD set the stage for the emergence of key vertebrate functional novelties (such as complex brains, circulatory system, heart, bone, cartilage, musculature and adipose tissue). A full explanation of the impact of 2R on evolution, function and the flow of information in vertebrate signalling networks is likely to have practical consequences for regenerative medicine, stem cell therapies and cancer treatment.

Dataset Information

Extended DNA threading through a dual-engine motor module of the activating signal co-integrator 1 complex.

Publications

Extended DNA threading through a dual-engine motor module of the activating signal co-integrator 1 complex.

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