---
APC_amount: 12348 EUR
OA_place: publisher
OA_type: hybrid
_id: '18778'
abstract:
- lang: eng
text: Transcription by RNA polymerase II (Pol II) can be repressed by noncoding
RNA, including the human RNA Alu. However, the mechanism by which endogenous RNAs
repress transcription remains unclear. Here we present cryogenic-electron microscopy
structures of Pol II bound to Alu RNA, which reveal that Alu RNA mimics how DNA
and RNA bind to Pol II during transcription elongation. Further, we show how distinct
domains of the general transcription factor TFIIF control repressive activity.
Together, we reveal how a noncoding RNA can regulate mammalian gene expression.
acknowledged_ssus:
- _id: LifeSc
- _id: EM-Fac
- _id: ScienComp
- _id: PreCl
acknowledgement: We thank the members of the Bernecky laboratory for helpful discussions
and A. Hlavata for providing Pol II for use in the fluorescence anisotropy binding
assay. We thank V.-V. Hodirnau for SerialEM data collection and support with EPU
data collection. We thank D. Slade (Max Perutz Laboratories and Medical University
of Vienna, Vienna, Austria) for the wild-type TFIIF expression plasmid. We thank
N. Thompson and R. Burgess (McArdle Laboratory for Cancer Research, University of
Wisconsin-Madison, Madison, WI, USA) for the 8WG16 hybridoma cell line. We thank
C. Plaschka and M. Loose for critical reading of the manuscript. This work was supported
by Austrian Science Fund (FWF) grant no. P34185 (DOI 10.55776/P34185) (C.B.). The
funders had no role in study design, data collection and analysis, decision to publish
or preparation of the manuscript. This research was further supported by the Scientific
Service Units of ISTA through resources provided by the Laboratory Support Facility,
Electron Microscopy Facility, Scientific Computing and the Preclinical Facility.
article_processing_charge: Yes (in subscription journal)
article_type: original
author:
- first_name: Katarina
full_name: Tluckova, Katarina
id: 4AC7D980-F248-11E8-B48F-1D18A9856A87
last_name: Tluckova
- first_name: Beata M
full_name: Kaczmarek, Beata M
id: 36FA4AFA-F248-11E8-B48F-1D18A9856A87
last_name: Kaczmarek
- first_name: Anita P
full_name: Testa Salmazo, Anita P
id: 41F1F098-F248-11E8-B48F-1D18A9856A87
last_name: Testa Salmazo
- first_name: Carrie A
full_name: Bernecky, Carrie A
id: 2CB9DFE2-F248-11E8-B48F-1D18A9856A87
last_name: Bernecky
orcid: 0000-0003-0893-7036
citation:
ama: Tluckova K, Kaczmarek BM, Testa Salmazo AP, Bernecky C. Mechanism of mammalian
transcriptional repression by noncoding RNA. Nature Structural & Molecular
Biology. 2025;32:607-612. doi:10.1038/s41594-024-01448-7
apa: Tluckova, K., Kaczmarek, B. M., Testa Salmazo, A. P., & Bernecky, C. (2025).
Mechanism of mammalian transcriptional repression by noncoding RNA. Nature
Structural & Molecular Biology. Springer Nature. https://doi.org/10.1038/s41594-024-01448-7
chicago: Tluckova, Katarina, Beata M Kaczmarek, Anita P Testa Salmazo, and Carrie
Bernecky. “Mechanism of Mammalian Transcriptional Repression by Noncoding RNA.”
Nature Structural & Molecular Biology. Springer Nature, 2025. https://doi.org/10.1038/s41594-024-01448-7.
ieee: K. Tluckova, B. M. Kaczmarek, A. P. Testa Salmazo, and C. Bernecky, “Mechanism
of mammalian transcriptional repression by noncoding RNA,” Nature Structural
& Molecular Biology, vol. 32. Springer Nature, pp. 607–612, 2025.
ista: Tluckova K, Kaczmarek BM, Testa Salmazo AP, Bernecky C. 2025. Mechanism of
mammalian transcriptional repression by noncoding RNA. Nature Structural &
Molecular Biology. 32, 607–612.
mla: Tluckova, Katarina, et al. “Mechanism of Mammalian Transcriptional Repression
by Noncoding RNA.” Nature Structural & Molecular Biology, vol. 32,
Springer Nature, 2025, pp. 607–12, doi:10.1038/s41594-024-01448-7.
short: K. Tluckova, B.M. Kaczmarek, A.P. Testa Salmazo, C. Bernecky, Nature Structural
& Molecular Biology 32 (2025) 607–612.
corr_author: '1'
date_created: 2025-01-08T11:20:20Z
date_published: 2025-04-01T00:00:00Z
date_updated: 2025-11-20T10:28:36Z
day: '01'
ddc:
- '570'
department:
- _id: CaBe
doi: 10.1038/s41594-024-01448-7
external_id:
isi:
- '001390268000001'
pmid:
- '39762629'
file:
- access_level: open_access
checksum: 2919b30b271f395888e880076a680d73
content_type: application/pdf
creator: dernst
date_created: 2025-04-16T08:17:27Z
date_updated: 2025-04-16T08:17:27Z
file_id: '19573'
file_name: 2025_NatureStrucMolBiol_Tluckova.pdf
file_size: 9306639
relation: main_file
success: 1
file_date_updated: 2025-04-16T08:17:27Z
fulldoi: https://doi.org/10.1038/s41594-024-01448-7
has_accepted_license: '1'
intvolume: ' 32'
isi: 1
language:
- iso: eng
license: https://creativecommons.org/licenses/by/4.0/
month: '04'
oa: 1
oa_version: Published Version
page: 607-612
pmid: 1
project:
- _id: c08a6700-5a5b-11eb-8a69-82a722b2bc30
grant_number: P34185
name: Regulation of mammalian transcription by noncoding RNA
publication: Nature Structural & Molecular Biology
publication_identifier:
eissn:
- 1545-9985
issn:
- 1545-9993
publication_status: published
publisher: Springer Nature
quality_controlled: '1'
related_material:
record:
- id: '14644'
relation: earlier_version
status: public
scopus_import: '1'
status: public
title: Mechanism of mammalian transcriptional repression by noncoding RNA
tmp:
image: /images/cc_by.png
legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
short: CC BY (4.0)
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 32
year: '2025'
...
---
OA_place: publisher
OA_type: hybrid
_id: '18553'
abstract:
- lang: eng
text: Transcription-coupled nucleotide excision repair (TC-NER) efficiently eliminates
DNA damage that impedes gene transcription by RNA polymerase II (RNA Pol II).
TC-NER is initiated by the recognition of lesion-stalled RNA Pol II by CSB, which
recruits the CRL4CSA ubiquitin ligase and UVSSA. RNA Pol II ubiquitylation at
RPB1-K1268 by CRL4CSA serves as a critical TC-NER checkpoint, governing RNA Pol
II stability and initiating DNA damage excision by TFIIH recruitment. However,
the precise regulatory mechanisms of CRL4CSA activity and TFIIH recruitment remain
elusive. Here, we reveal human serine/threonine-protein kinase 19 (STK19) as a
TC-NER factor, which is essential for correct DNA damage removal and subsequent
transcription restart. Cryogenic electron microscopy (cryo-EM) studies demonstrate
that STK19 is an integral part of the RNA Pol II-TC-NER complex, bridging CSA,
UVSSA, RNA Pol II, and downstream DNA. STK19 stimulates TC-NER complex stability
and CRL4CSA activity, resulting in efficient RNA Pol II ubiquitylation and correct
UVSSA and TFIIH binding. These findings underscore the crucial role of STK19 as
a core TC-NER component.
acknowledged_ssus:
- _id: LifeSc
- _id: PreCl
acknowledgement: We thank N. Thompson and R. Burgess for the 8WG16 hybridoma cell
line. This research was further supported by the Scientific Service Units (SSU)
of IST Austria through resources provided by the Lab Support Facility (LSF) and
the Preclinical Facility (PCF). This work is part of the Oncode Institute, which
is partly financed by the Dutch Cancer Society. Research at the Netherlands Cancer
Institute is supported by institutional grants of the Dutch Cancer Society and the
Dutch Ministry of Health, Welfare and Sport. This study was supported by a VICI
(VI.C.182.025) and a TOP Grant (714.017.003) of the Netherlands Organization for
Scientific Research.
article_processing_charge: No
article_type: original
author:
- first_name: Anisha R.
full_name: Ramadhin, Anisha R.
last_name: Ramadhin
- first_name: Shun-Hsiao
full_name: Lee, Shun-Hsiao
last_name: Lee
- first_name: Di
full_name: Zhou, Di
last_name: Zhou
- first_name: Anita P
full_name: Testa Salmazo, Anita P
id: 41F1F098-F248-11E8-B48F-1D18A9856A87
last_name: Testa Salmazo
- first_name: Camila
full_name: Gonzalo-Hansen, Camila
last_name: Gonzalo-Hansen
- first_name: Marjolein
full_name: van Sluis, Marjolein
last_name: van Sluis
- first_name: Cindy M.A.
full_name: Blom, Cindy M.A.
last_name: Blom
- first_name: Roel C.
full_name: Janssens, Roel C.
last_name: Janssens
- first_name: Anja
full_name: Raams, Anja
last_name: Raams
- first_name: Dick
full_name: Dekkers, Dick
last_name: Dekkers
- first_name: Karel
full_name: Bezstarosti, Karel
last_name: Bezstarosti
- first_name: Dea
full_name: Slade, Dea
last_name: Slade
- first_name: Wim
full_name: Vermeulen, Wim
last_name: Vermeulen
- first_name: Alex
full_name: Pines, Alex
last_name: Pines
- first_name: Jeroen A.A.
full_name: Demmers, Jeroen A.A.
last_name: Demmers
- first_name: Carrie A
full_name: Bernecky, Carrie A
id: 2CB9DFE2-F248-11E8-B48F-1D18A9856A87
last_name: Bernecky
orcid: 0000-0003-0893-7036
- first_name: Titia K.
full_name: Sixma, Titia K.
last_name: Sixma
- first_name: Jurgen A.
full_name: Marteijn, Jurgen A.
last_name: Marteijn
citation:
ama: Ramadhin AR, Lee S-H, Zhou D, et al. STK19 drives transcription-coupled repair
by stimulating repair complex stability, RNA Pol II ubiquitylation, and TFIIH
recruitment. Molecular Cell. 2024;84(24):4740-4757.e12. doi:10.1016/j.molcel.2024.10.030
apa: Ramadhin, A. R., Lee, S.-H., Zhou, D., Testa Salmazo, A. P., Gonzalo-Hansen,
C., van Sluis, M., … Marteijn, J. A. (2024). STK19 drives transcription-coupled
repair by stimulating repair complex stability, RNA Pol II ubiquitylation, and
TFIIH recruitment. Molecular Cell. Elsevier. https://doi.org/10.1016/j.molcel.2024.10.030
chicago: Ramadhin, Anisha R., Shun-Hsiao Lee, Di Zhou, Anita P Testa Salmazo, Camila
Gonzalo-Hansen, Marjolein van Sluis, Cindy M.A. Blom, et al. “STK19 Drives Transcription-Coupled
Repair by Stimulating Repair Complex Stability, RNA Pol II Ubiquitylation, and
TFIIH Recruitment.” Molecular Cell. Elsevier, 2024. https://doi.org/10.1016/j.molcel.2024.10.030.
ieee: A. R. Ramadhin et al., “STK19 drives transcription-coupled repair by
stimulating repair complex stability, RNA Pol II ubiquitylation, and TFIIH recruitment,”
Molecular Cell, vol. 84, no. 24. Elsevier, p. 4740–4757.e12, 2024.
ista: Ramadhin AR, Lee S-H, Zhou D, Testa Salmazo AP, Gonzalo-Hansen C, van Sluis
M, Blom CMA, Janssens RC, Raams A, Dekkers D, Bezstarosti K, Slade D, Vermeulen
W, Pines A, Demmers JAA, Bernecky C, Sixma TK, Marteijn JA. 2024. STK19 drives
transcription-coupled repair by stimulating repair complex stability, RNA Pol
II ubiquitylation, and TFIIH recruitment. Molecular Cell. 84(24), 4740–4757.e12.
mla: Ramadhin, Anisha R., et al. “STK19 Drives Transcription-Coupled Repair by Stimulating
Repair Complex Stability, RNA Pol II Ubiquitylation, and TFIIH Recruitment.” Molecular
Cell, vol. 84, no. 24, Elsevier, 2024, p. 4740–4757.e12, doi:10.1016/j.molcel.2024.10.030.
short: A.R. Ramadhin, S.-H. Lee, D. Zhou, A.P. Testa Salmazo, C. Gonzalo-Hansen,
M. van Sluis, C.M.A. Blom, R.C. Janssens, A. Raams, D. Dekkers, K. Bezstarosti,
D. Slade, W. Vermeulen, A. Pines, J.A.A. Demmers, C. Bernecky, T.K. Sixma, J.A.
Marteijn, Molecular Cell 84 (2024) 4740–4757.e12.
das_tickbox: '1'
dataavailabilitystatement: "Proteomics data is deposited at the ProteomeXchange Consortium
through the PRIDE partner repository with dataset identifier PXD051720. Imaging
data are deposited at Mendeley Data at https://doi.org/10.17632/wp9sf6sp4z.1. Cryo-EM
reconstructions and structure coordinates are deposited to the Electron Microscopy
Database (EMDB) and to the PDB under the following accession codes: for RNA Pol
II-TC-NER-STK19 complex model (PDB: 9FD2), composite map (EMD-50325) and consensus
map (EMD-50292). Focused maps of CSA-DDB1-DDA1-UVSSA-STK19 (EMD-50293), RNA Pol
II-ELOF1 (EMD-50294), CRL4CSA (EMD-50295), and CSA-DDB1-DDA1-CSB (EMD-50306).\r\nThis
paper does not report original code.\r\nAny additional information required to reanalyze
the data reported in this paper is available from the lead contact upon request."
date_created: 2024-11-15T12:12:54Z
date_published: 2024-12-19T00:00:00Z
date_updated: 2026-10-01T08:20:39Z
day: '19'
ddc:
- '570'
department:
- _id: CaBe
doi: 10.1016/j.molcel.2024.10.030
external_id:
isi:
- '001395711300001'
pmid:
- '39547223'
file:
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checksum: e051e2766b2d424983778f742cb7c5ed
content_type: application/pdf
creator: dernst
date_created: 2025-01-13T11:17:35Z
date_updated: 2025-01-13T11:17:35Z
file_id: '18844'
file_name: 2024_MolecularCell_Ramadhin.pdf
file_size: 25071994
relation: main_file
success: 1
file_date_updated: 2025-01-13T11:17:35Z
fulldoi: https://doi.org/10.1016/j.molcel.2024.10.030
has_accepted_license: '1'
intvolume: ' 84'
isi: 1
issue: '24'
language:
- iso: eng
month: '12'
oa: 1
oa_version: Published Version
page: 4740-4757.e12
pmid: 1
publication: Molecular Cell
publication_identifier:
issn:
- 1097-2765
publication_status: published
publisher: Elsevier
quality_controlled: '1'
related_material:
record:
- id: '23013'
relation: research_data
status: public
researchdata_availability: yes
scopus_import: '1'
status: public
supplementarymaterial: yes
title: STK19 drives transcription-coupled repair by stimulating repair complex stability,
RNA Pol II ubiquitylation, and TFIIH recruitment
tmp:
image: /images/cc_by.png
legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
short: CC BY (4.0)
type: journal_article
user_id: 317138e5-6ab7-11ef-aa6d-ffef3953e345
volume: 84
year: '2024'
...
---
OA_type: closed access
_id: '18945'
abstract:
- lang: eng
text: Vaccinia-related kinase 1 (VRK1) and the δ and ε isoforms of casein kinase
1 (CK1) are linked to various disease-relevant pathways. However, the lack of
tool compounds for these kinases has significantly hampered our understanding
of their cellular functions and therapeutic potential. Here, we describe the structure-based
development of potent inhibitors of VRK1, a kinase highly expressed in various
tumor types and crucial for cell proliferation and genome integrity. Kinome-wide
profiling revealed that our compounds also inhibit CK1δ and CK1ε. We demonstrate
that dihydropteridinones 35 and 36 mimic the cellular outcomes of VRK1 depletion.
Complementary studies with existing CK1δ and CK1ε inhibitors suggest that these
kinases may play overlapping roles in cell proliferation and genome instability.
Together, our findings highlight the potential of VRK1 inhibition in treating
p53-deficient tumors and possibly enhancing the efficacy of existing cancer therapies
that target DNA stability or cell division.
acknowledgement: "R.M.C. and K.B.M. are grateful for support by FAPESP (Fundação de
Amparo à Pesquisa do Estado de São Paulo) (grants 2013/50724–5 and 2014/50897–0),
Embrapii (Empresa Brasileira de Pesquisa e Inovação Industrial), CNPq (Conselho
Nacional de Desenvolvimento Científico e Tecnológico) (grant 465651/2014–3) and
Aché Laboratórios Farmacêuticos. R.M.C. and O.G. are also grateful for support by
the Structural Genomics Consortium, a registered charity (1097737) that receives
funds from AbbVie, Bayer AG, Boehringer Ingelheim, Canada Foundation for Innovation,
Eshelman Institute for Innovation, Genentech, Genome Canada through the Ontario
Genomics Institute (OGI-196), EU/EFPIA/OICR/McGill/KTH/Diamond, Innovative Medicines
Initiative 2 Joint Undertaking (EUbOPEN Grant 875510), Janssen, Merck KGaA, Merck
& Co., Pfizer, Takeda, and Wellcome. B.L. and M.H. are grateful for support from
the Swedish Research Council, Swedish Cancer Society, Karolinska Institutet and
The Mark Foundation for Cancer Research. R.A.M.S. (2016/25320–6 and 2018/23322–7),
A.S.S. (2019/14275–8), S.N.S.V (2018/09475–5), V.M.A. (2022/00743–2) and M.R.C.
(2021/04853–4) were recipients of fellowships from the Fundação de Amparo à Pesquisa
do Estado de São Paulo, FAPESP. C.V.R. (88887.146077/2017–00), J.E.T. (88887.373547/2019–00)
and P.Z.R (88887.136432/2017–00) were the recipient of fellowships from the Coordenação
de Aperfeiçoamento de Pessoal de Nível Superior, CAPES.\r\nWe thank all members
of CQMED-UNICAMP for their help and support. We thank the staff of the Life Sciences
Core Facility (LaCTAD) at UNICAMP for the Genomics and Mass Spectrometry analysis.
We thank the NMR facility at UNICAMP Chemistry Institute for its assistance. We
thank the staff at the Northeastern Collaborative Access Team beamlines, which are
funded by the National Institute of General Medical Sciences from the National Institutes
of Health (P41 GM103403). The Pilatus 6M detector on the 24-ID-C beamline is funded
by a NIH-ORIP HEI grant (S10 RR029205). This research used resources of the Advanced
Photon Source; a U.S. Department of Energy (DOE) Office of Science User Facility
operated for the DOE Office of Science by Argonne National Laboratory under Contract
No. DE-AC02-06CH11357. We thank Diamond Light Source for access to beamline I24.
The authors thank Tammy Havener (SGC-UNC), Abid Hussain Sayyid (KI), and Yiqiu Yang
(KI) for valuable discussions and technical support."
article_processing_charge: No
article_type: original
author:
- first_name: Fernando H.
full_name: de Souza Gama, Fernando H.
last_name: de Souza Gama
- first_name: Luiz A.
full_name: Dutra, Luiz A.
last_name: Dutra
- first_name: Michael
full_name: Hawgood, Michael
last_name: Hawgood
- first_name: Caio Vinícius
full_name: dos Reis, Caio Vinícius
last_name: dos Reis
- first_name: Ricardo A. M.
full_name: Serafim, Ricardo A. M.
last_name: Serafim
- first_name: Marcos A.
full_name: Ferreira, Marcos A.
last_name: Ferreira
- first_name: Bruno V. M.
full_name: Teodoro, Bruno V. M.
last_name: Teodoro
- first_name: Jéssica Emi
full_name: Takarada, Jéssica Emi
last_name: Takarada
- first_name: André S.
full_name: Santiago, André S.
last_name: Santiago
- first_name: Dimitrios-Ilias
full_name: Balourdas, Dimitrios-Ilias
last_name: Balourdas
- first_name: Ann-Sofie
full_name: Nilsson, Ann-Sofie
last_name: Nilsson
- first_name: Bruno
full_name: Urien, Bruno
last_name: Urien
- first_name: Vitor M.
full_name: Almeida, Vitor M.
last_name: Almeida
- first_name: Carina
full_name: Gileadi, Carina
last_name: Gileadi
- first_name: Priscila Z.
full_name: Ramos, Priscila Z.
last_name: Ramos
- first_name: Anita P
full_name: Testa Salmazo, Anita P
id: 41F1F098-F248-11E8-B48F-1D18A9856A87
last_name: Testa Salmazo
- first_name: Stanley N. S.
full_name: Vasconcelos, Stanley N. S.
last_name: Vasconcelos
- first_name: Micael R.
full_name: Cunha, Micael R.
last_name: Cunha
- first_name: Susanne
full_name: Mueller, Susanne
last_name: Mueller
- first_name: Stefan
full_name: Knapp, Stefan
last_name: Knapp
- first_name: Katlin B.
full_name: Massirer, Katlin B.
last_name: Massirer
- first_name: Jonathan M.
full_name: Elkins, Jonathan M.
last_name: Elkins
- first_name: Opher
full_name: Gileadi, Opher
last_name: Gileadi
- first_name: Alessandra
full_name: Mascarello, Alessandra
last_name: Mascarello
- first_name: Bennie B. L. G.
full_name: Lemmens, Bennie B. L. G.
last_name: Lemmens
- first_name: Cristiano R. W.
full_name: Guimarães, Cristiano R. W.
last_name: Guimarães
- first_name: Hatylas
full_name: Azevedo, Hatylas
last_name: Azevedo
- first_name: Rafael M.
full_name: Couñago, Rafael M.
last_name: Couñago
citation:
ama: de Souza Gama FH, Dutra LA, Hawgood M, et al. Novel dihydropteridinone derivatives
as potent inhibitors of the understudied human kinases vaccinia-related kinase
1 and casein kinase 1δ/ε. Journal of Medicinal Chemistry. 2024;67(11):8609-8629.
doi:10.1021/acs.jmedchem.3c02250
apa: de Souza Gama, F. H., Dutra, L. A., Hawgood, M., dos Reis, C. V., Serafim,
R. A. M., Ferreira, M. A., … Couñago, R. M. (2024). Novel dihydropteridinone derivatives
as potent inhibitors of the understudied human kinases vaccinia-related kinase
1 and casein kinase 1δ/ε. Journal of Medicinal Chemistry. American Chemical
Society. https://doi.org/10.1021/acs.jmedchem.3c02250
chicago: Souza Gama, Fernando H. de, Luiz A. Dutra, Michael Hawgood, Caio Vinícius
dos Reis, Ricardo A. M. Serafim, Marcos A. Ferreira, Bruno V. M. Teodoro, et al.
“Novel Dihydropteridinone Derivatives as Potent Inhibitors of the Understudied
Human Kinases Vaccinia-Related Kinase 1 and Casein Kinase 1δ/ε.” Journal of
Medicinal Chemistry. American Chemical Society, 2024. https://doi.org/10.1021/acs.jmedchem.3c02250.
ieee: F. H. de Souza Gama et al., “Novel dihydropteridinone derivatives as
potent inhibitors of the understudied human kinases vaccinia-related kinase 1
and casein kinase 1δ/ε,” Journal of Medicinal Chemistry, vol. 67, no. 11.
American Chemical Society, pp. 8609–8629, 2024.
ista: de Souza Gama FH, Dutra LA, Hawgood M, dos Reis CV, Serafim RAM, Ferreira
MA, Teodoro BVM, Takarada JE, Santiago AS, Balourdas D-I, Nilsson A-S, Urien B,
Almeida VM, Gileadi C, Ramos PZ, Testa Salmazo AP, Vasconcelos SNS, Cunha MR,
Mueller S, Knapp S, Massirer KB, Elkins JM, Gileadi O, Mascarello A, Lemmens BBLG,
Guimarães CRW, Azevedo H, Couñago RM. 2024. Novel dihydropteridinone derivatives
as potent inhibitors of the understudied human kinases vaccinia-related kinase
1 and casein kinase 1δ/ε. Journal of Medicinal Chemistry. 67(11), 8609–8629.
mla: de Souza Gama, Fernando H., et al. “Novel Dihydropteridinone Derivatives as
Potent Inhibitors of the Understudied Human Kinases Vaccinia-Related Kinase 1
and Casein Kinase 1δ/ε.” Journal of Medicinal Chemistry, vol. 67, no. 11,
American Chemical Society, 2024, pp. 8609–29, doi:10.1021/acs.jmedchem.3c02250.
short: F.H. de Souza Gama, L.A. Dutra, M. Hawgood, C.V. dos Reis, R.A.M. Serafim,
M.A. Ferreira, B.V.M. Teodoro, J.E. Takarada, A.S. Santiago, D.-I. Balourdas,
A.-S. Nilsson, B. Urien, V.M. Almeida, C. Gileadi, P.Z. Ramos, A.P. Testa Salmazo,
S.N.S. Vasconcelos, M.R. Cunha, S. Mueller, S. Knapp, K.B. Massirer, J.M. Elkins,
O. Gileadi, A. Mascarello, B.B.L.G. Lemmens, C.R.W. Guimarães, H. Azevedo, R.M.
Couñago, Journal of Medicinal Chemistry 67 (2024) 8609–8629.
das_tickbox: '1'
dataavailabilitystatement: 'Atomic coordinates and experimental data have been deposited
in the PDB with the following PDB ID codes: 6CNX (VRK1 bound to 2); 6CFM (VRK1 bound
to 3); 6CQH (VRK1 bound to 4); 6CMM (VRK1 bound to 7); 6VXU (VRK1 bound to 8); 6VZH
(VRK1 bound to 11); 6CSW (VRK1 bound to 13); 8V42 (VRK1 bound to 21); 6NPN (VRK1
bound to 24).'
date_created: 2025-01-29T09:14:19Z
date_published: 2024-05-23T00:00:00Z
date_updated: 2026-10-01T08:26:28Z
day: '23'
department:
- _id: CaBe
doi: 10.1021/acs.jmedchem.3c02250
external_id:
pmid:
- '38780468'
fulldoi: https://doi.org/10.1021/acs.jmedchem.3c02250
intvolume: ' 67'
issue: '11'
language:
- iso: eng
month: '05'
oa_version: None
page: 8609-8629
pmid: 1
publication: Journal of Medicinal Chemistry
publication_identifier:
eissn:
- 1520-4804
issn:
- 0022-2623
publication_status: published
publisher: American Chemical Society
quality_controlled: '1'
researchdata_availability: yes
scopus_import: '1'
status: public
supplementarymaterial: yes
title: Novel dihydropteridinone derivatives as potent inhibitors of the understudied
human kinases vaccinia-related kinase 1 and casein kinase 1δ/ε
type: journal_article
user_id: 317138e5-6ab7-11ef-aa6d-ffef3953e345
volume: 67
year: '2024'
...
---
_id: '14644'
abstract:
- lang: eng
text: Transcription by RNA polymerase II (Pol II) can be repressed by noncoding
RNA, including the human RNA Alu. However, the mechanism by which endogenous RNAs
repress transcription remains unclear. Here we present cryo-electron microscopy
structures of Pol II bound to Alu RNA, which reveal that Alu RNA mimics how DNA
and RNA bind to Pol II during transcription elongation. Further, we show how domains
of the general transcription factor TFIIF affect complex dynamics and control
repressive activity. Together, we reveal how a non-coding RNA can regulate mammalian
gene expression.
acknowledged_ssus:
- _id: LifeSc
- _id: EM-Fac
- _id: PreCl
acknowledgement: "We thank B. Kaczmarek and other members of the Bernecky lab for
helpful discussions. We thank V.-V. Hodirnau for SerialEM data collection and support
with EPU data collection. We thank D. Slade for the wild type TFIIF expression\r\nplasmid.
We thank N. Thompson and R. Burgess for the 8WG16 hybridoma cell line. We thank
C. Plaschka and M. Loose for critical reading of the manuscript. This work was supported
by Austrian Science Fund (FWF) grant P34185. This research was further supported
by the Scientific Service Units (SSU) of IST Austria through resources provided
by the Lab Support Facility (LSF), Electron Microscopy Facility (EMF), Scientific
Computing (SciComp), and the Preclinical Facility (PCF)."
article_processing_charge: No
author:
- first_name: Katarina
full_name: Tluckova, Katarina
id: 4AC7D980-F248-11E8-B48F-1D18A9856A87
last_name: Tluckova
- first_name: Anita P
full_name: Testa Salmazo, Anita P
id: 41F1F098-F248-11E8-B48F-1D18A9856A87
last_name: Testa Salmazo
- first_name: Carrie A
full_name: Bernecky, Carrie A
id: 2CB9DFE2-F248-11E8-B48F-1D18A9856A87
last_name: Bernecky
orcid: 0000-0003-0893-7036
citation:
ama: Tluckova K, Testa Salmazo AP, Bernecky C. Mechanism of mammalian transcriptional
repression by noncoding RNA. doi:10.15479/AT:ISTA:14644
apa: Tluckova, K., Testa Salmazo, A. P., & Bernecky, C. (n.d.). Mechanism of
mammalian transcriptional repression by noncoding RNA. Institute of Science and
Technology Austria. https://doi.org/10.15479/AT:ISTA:14644
chicago: Tluckova, Katarina, Anita P Testa Salmazo, and Carrie Bernecky. “Mechanism
of Mammalian Transcriptional Repression by Noncoding RNA.” Institute of Science
and Technology Austria, n.d. https://doi.org/10.15479/AT:ISTA:14644.
ieee: K. Tluckova, A. P. Testa Salmazo, and C. Bernecky, “Mechanism of mammalian
transcriptional repression by noncoding RNA.” Institute of Science and Technology
Austria.
ista: Tluckova K, Testa Salmazo AP, Bernecky C. Mechanism of mammalian transcriptional
repression by noncoding RNA. 10.15479/AT:ISTA:14644.
mla: Tluckova, Katarina, et al. Mechanism of Mammalian Transcriptional Repression
by Noncoding RNA. Institute of Science and Technology Austria, doi:10.15479/AT:ISTA:14644.
short: K. Tluckova, A.P. Testa Salmazo, C. Bernecky, (n.d.).
corr_author: '1'
date_created: 2023-12-04T14:51:00Z
date_published: 2023-12-05T00:00:00Z
date_updated: 2025-11-20T10:28:37Z
day: '05'
ddc:
- '572'
doi: 10.15479/AT:ISTA:14644
file:
- access_level: open_access
checksum: c45608cb97ee36d7b50ba518db8e07b0
content_type: application/pdf
creator: dernst
date_created: 2023-12-05T10:37:02Z
date_updated: 2023-12-05T10:37:02Z
file_id: '14646'
file_name: 2023_Tluckova_etal_REx.pdf
file_size: 4892920
relation: main_file
success: 1
file_date_updated: 2023-12-05T10:37:02Z
fulldoi: https://doi.org/10.15479/AT:ISTA:14644
has_accepted_license: '1'
language:
- iso: eng
license: https://creativecommons.org/licenses/by-nc/4.0/
month: '12'
oa: 1
oa_version: Submitted Version
project:
- _id: c08a6700-5a5b-11eb-8a69-82a722b2bc30
grant_number: P34185
name: Regulation of mammalian transcription by noncoding RNA
publication_status: draft
publisher: Institute of Science and Technology Austria
related_material:
record:
- id: '18778'
relation: later_version
status: public
status: public
title: Mechanism of mammalian transcriptional repression by noncoding RNA
tmp:
image: /images/cc_by_nc.png
legal_code_url: https://creativecommons.org/licenses/by-nc/4.0/legalcode
name: Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)
short: CC BY-NC (4.0)
type: preprint
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
year: '2023'
...
---
_id: '15061'
abstract:
- lang: eng
text: The actin cytoskeleton, a dynamic network of actin filaments and associated
F-actin–binding proteins, is fundamentally important in eukaryotes. α-Actinins
are major F-actin bundlers that are inhibited by Ca2+ in nonmuscle cells. Here
we report the mechanism of Ca2+-mediated regulation of Entamoeba histolytica α-actinin-2
(EhActn2) with features expected for the common ancestor of Entamoeba and higher
eukaryotic α-actinins. Crystal structures of Ca2+-free and Ca2+-bound EhActn2
reveal a calmodulin-like domain (CaMD) uniquely inserted within the rod domain.
Integrative studies reveal an exceptionally high affinity of the EhActn2 CaMD
for Ca2+, binding of which can only be regulated in the presence of physiological
concentrations of Mg2+. Ca2+ binding triggers an increase in protein multidomain
rigidity, reducing conformational flexibility of F-actin–binding domains via interdomain
cross-talk and consequently inhibiting F-actin bundling. In vivo studies uncover
that EhActn2 plays an important role in phagocytic cup formation and might constitute
a new drug target for amoebic dysentery.
acknowledged_ssus:
- _id: LifeSc
acknowledgement: "We thank the staff of the macromolecular crystallography (MX) and
SAXS beamlines at the European Synchrotron Radiation facility, Diamond, and Swiss
Light Source for excellent support, and the Life Sciences Facility of the Institute
of Science and Technology Austria for usage of the rheometer. We thank Life Sciences
editors for editing assistance. EM data were\r\nrecorded at the EM Facility of the
Vienna BioCenter Core Facilities (Austria). Confocal microscopy was carried out
at the Advanced Instrument Research Facility, Jawaharlal Nehru University. K.D.-C.’s
research was supported by the Initial Training Network MUZIC (ITN-MUZIC) (N°238423),
Austrian Science Fund (FWF) Projects I525, I1593, P22276, P19060, and W1221, Laura
Bassi Centre of Optimized Structural Studies (N°253275), a Wellcome Trust Collaborative
Award (201543/Z/16/Z), COST Action BM1405, Vienna Science and Technology Fund (WWTF)
Chemical Biology Project LS17-008, and Christian Doppler Laboratory for High-Content
Structural Biology and Biotechnology. K.Z., J.L.A., C.S., E.A.G., and A.S. were
supported by the University of Vienna, J.K. by a Wellcome Trust Collaborative Award
and by the Centre of Optimized Structural Studies, M.P. by FWF Project I1593, E.d.A.R.
ITN-MUZIC, and FWF Projects I525 and I1593, and T.C.M. and L.C. by FWF Project I
2408-B22. E.A.G. acknowledges the PhD program Structure and Interaction of Biological
Macromolecules. M.B. acknowledges the University Grant Commission, India, for a
senior research fellowship. A.B. acknowledges a JC Bose Fellowship from the Science
Engineering Research Council. "
article_processing_charge: No
article_type: original
author:
- first_name: Nikos
full_name: Pinotsis, Nikos
last_name: Pinotsis
- first_name: Karolina
full_name: Zielinska, Karolina
last_name: Zielinska
- first_name: Mrigya
full_name: Babuta, Mrigya
last_name: Babuta
- first_name: Joan L.
full_name: Arolas, Joan L.
last_name: Arolas
- first_name: Julius
full_name: Kostan, Julius
last_name: Kostan
- first_name: Muhammad Bashir
full_name: Khan, Muhammad Bashir
last_name: Khan
- first_name: Claudia
full_name: Schreiner, Claudia
last_name: Schreiner
- first_name: Anita P
full_name: Testa Salmazo, Anita P
id: 41F1F098-F248-11E8-B48F-1D18A9856A87
last_name: Testa Salmazo
- first_name: Luciano
full_name: Ciccarelli, Luciano
last_name: Ciccarelli
- first_name: Martin
full_name: Puchinger, Martin
last_name: Puchinger
- first_name: Eirini A.
full_name: Gkougkoulia, Eirini A.
last_name: Gkougkoulia
- first_name: Euripedes de Almeida
full_name: Ribeiro, Euripedes de Almeida
last_name: Ribeiro
- first_name: Thomas C.
full_name: Marlovits, Thomas C.
last_name: Marlovits
- first_name: Alok
full_name: Bhattacharya, Alok
last_name: Bhattacharya
- first_name: Kristina
full_name: Djinovic-Carugo, Kristina
last_name: Djinovic-Carugo
citation:
ama: Pinotsis N, Zielinska K, Babuta M, et al. Calcium modulates the domain flexibility
and function of an α-actinin similar to the ancestral α-actinin. Proceedings
of the National Academy of Sciences of the United States of America. 2020;117(36):22101-22112.
doi:10.1073/pnas.1917269117
apa: Pinotsis, N., Zielinska, K., Babuta, M., Arolas, J. L., Kostan, J., Khan, M.
B., … Djinovic-Carugo, K. (2020). Calcium modulates the domain flexibility and
function of an α-actinin similar to the ancestral α-actinin. Proceedings of
the National Academy of Sciences of the United States of America. National
Academy of Sciences. https://doi.org/10.1073/pnas.1917269117
chicago: Pinotsis, Nikos, Karolina Zielinska, Mrigya Babuta, Joan L. Arolas, Julius
Kostan, Muhammad Bashir Khan, Claudia Schreiner, et al. “Calcium Modulates the
Domain Flexibility and Function of an α-Actinin Similar to the Ancestral α-Actinin.”
Proceedings of the National Academy of Sciences of the United States of America.
National Academy of Sciences, 2020. https://doi.org/10.1073/pnas.1917269117.
ieee: N. Pinotsis et al., “Calcium modulates the domain flexibility and function
of an α-actinin similar to the ancestral α-actinin,” Proceedings of the National
Academy of Sciences of the United States of America, vol. 117, no. 36. National
Academy of Sciences, pp. 22101–22112, 2020.
ista: Pinotsis N, Zielinska K, Babuta M, Arolas JL, Kostan J, Khan MB, Schreiner
C, Testa Salmazo AP, Ciccarelli L, Puchinger M, Gkougkoulia EA, Ribeiro E de A,
Marlovits TC, Bhattacharya A, Djinovic-Carugo K. 2020. Calcium modulates the domain
flexibility and function of an α-actinin similar to the ancestral α-actinin. Proceedings
of the National Academy of Sciences of the United States of America. 117(36),
22101–22112.
mla: Pinotsis, Nikos, et al. “Calcium Modulates the Domain Flexibility and Function
of an α-Actinin Similar to the Ancestral α-Actinin.” Proceedings of the National
Academy of Sciences of the United States of America, vol. 117, no. 36, National
Academy of Sciences, 2020, pp. 22101–12, doi:10.1073/pnas.1917269117.
short: N. Pinotsis, K. Zielinska, M. Babuta, J.L. Arolas, J. Kostan, M.B. Khan,
C. Schreiner, A.P. Testa Salmazo, L. Ciccarelli, M. Puchinger, E.A. Gkougkoulia,
E. de A. Ribeiro, T.C. Marlovits, A. Bhattacharya, K. Djinovic-Carugo, Proceedings
of the National Academy of Sciences of the United States of America 117 (2020)
22101–22112.
date_created: 2024-03-04T10:03:52Z
date_published: 2020-09-08T00:00:00Z
date_updated: 2026-06-18T17:45:21Z
day: '08'
ddc:
- '570'
department:
- _id: CaBe
doi: 10.1073/pnas.1917269117
external_id:
pmid:
- '32848067'
fulldoi: https://doi.org/10.1073/pnas.1917269117
intvolume: ' 117'
issue: '36'
language:
- iso: eng
main_file_link:
- open_access: '1'
url: https://doi.org/10.1073/pnas.191726911
month: '09'
oa: 1
oa_version: Published Version
page: 22101-22112
pmid: 1
publication: Proceedings of the National Academy of Sciences of the United States
of America
publication_identifier:
eissn:
- 1091-6490
issn:
- 0027-8424
publication_status: published
publisher: National Academy of Sciences
quality_controlled: '1'
status: public
title: Calcium modulates the domain flexibility and function of an α-actinin similar
to the ancestral α-actinin
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 117
year: '2020'
...