@article{18778,
  abstract     = {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.},
  author       = {Tluckova, Katarina and Kaczmarek, Beata M and Testa Salmazo, Anita P and Bernecky, Carrie A},
  issn         = {1545-9985},
  journal      = {Nature Structural & Molecular Biology},
  pages        = {607--612},
  publisher    = {Springer Nature},
  title        = {{Mechanism of mammalian transcriptional repression by noncoding RNA}},
  doi          = {10.1038/s41594-024-01448-7},
  volume       = {32},
  year         = {2025},
}

@article{18553,
  abstract     = {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.},
  author       = {Ramadhin, Anisha R. and Lee, Shun-Hsiao and Zhou, Di and Testa Salmazo, Anita P and Gonzalo-Hansen, Camila and van Sluis, Marjolein and Blom, Cindy M.A. and Janssens, Roel C. and Raams, Anja and Dekkers, Dick and Bezstarosti, Karel and Slade, Dea and Vermeulen, Wim and Pines, Alex and Demmers, Jeroen A.A. and Bernecky, Carrie A and Sixma, Titia K. and Marteijn, Jurgen A.},
  issn         = {1097-2765},
  journal      = {Molecular Cell},
  number       = {24},
  pages        = {4740--4757.e12},
  publisher    = {Elsevier},
  title        = {{STK19 drives transcription-coupled repair by stimulating repair complex stability, RNA Pol II ubiquitylation, and TFIIH recruitment}},
  doi          = {10.1016/j.molcel.2024.10.030},
  volume       = {84},
  year         = {2024},
}

@article{18945,
  abstract     = {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.},
  author       = {de Souza Gama, Fernando H. and Dutra, Luiz A. and Hawgood, Michael and dos Reis, Caio Vinícius and Serafim, Ricardo A. M. and Ferreira, Marcos A. and Teodoro, Bruno V. M. and Takarada, Jéssica Emi and Santiago, André S. and Balourdas, Dimitrios-Ilias and Nilsson, Ann-Sofie and Urien, Bruno and Almeida, Vitor M. and Gileadi, Carina and Ramos, Priscila Z. and Testa Salmazo, Anita P and Vasconcelos, Stanley N. S. and Cunha, Micael R. and Mueller, Susanne and Knapp, Stefan and Massirer, Katlin B. and Elkins, Jonathan M. and Gileadi, Opher and Mascarello, Alessandra and Lemmens, Bennie B. L. G. and Guimarães, Cristiano R. W. and Azevedo, Hatylas and Couñago, Rafael M.},
  issn         = {1520-4804},
  journal      = {Journal of Medicinal Chemistry},
  number       = {11},
  pages        = {8609--8629},
  publisher    = {American Chemical Society},
  title        = {{Novel dihydropteridinone derivatives as potent inhibitors of the understudied human kinases vaccinia-related kinase 1 and casein kinase 1δ/ε}},
  doi          = {10.1021/acs.jmedchem.3c02250},
  volume       = {67},
  year         = {2024},
}

@unpublished{14644,
  abstract     = {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.},
  author       = {Tluckova, Katarina and Testa Salmazo, Anita P and Bernecky, Carrie A},
  publisher    = {Institute of Science and Technology Austria},
  title        = {{Mechanism of mammalian transcriptional repression by noncoding RNA}},
  doi          = {10.15479/AT:ISTA:14644},
  year         = {2023},
}

@article{15061,
  abstract     = {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.},
  author       = {Pinotsis, Nikos and Zielinska, Karolina and Babuta, Mrigya and Arolas, Joan L. and Kostan, Julius and Khan, Muhammad Bashir and Schreiner, Claudia and Testa Salmazo, Anita P and Ciccarelli, Luciano and Puchinger, Martin and Gkougkoulia, Eirini A. and Ribeiro, Euripedes de Almeida and Marlovits, Thomas C. and Bhattacharya, Alok and Djinovic-Carugo, Kristina},
  issn         = {1091-6490},
  journal      = {Proceedings of the National Academy of Sciences of the United States of America},
  number       = {36},
  pages        = {22101--22112},
  publisher    = {National Academy of Sciences},
  title        = {{Calcium modulates the domain flexibility and function of an α-actinin similar to the ancestral α-actinin}},
  doi          = {10.1073/pnas.1917269117},
  volume       = {117},
  year         = {2020},
}