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HELLS regulates transcription in T-cell lymphomas by reducing unscheduled R-loops and by facilitating RNAPII progression.
Tameni, Annalisa; Mallia, Selene; Manicardi, Veronica; Donati, Benedetta; Torricelli, Federica; Vitale, Emanuele; Salviato, Elisa; Gambarelli, Giulia; Muccioli, Silvia; Zanelli, Magda; Ascani, Stefano; Martino, Giovanni; Sanguedolce, Francesca; Sauta, Elisabetta; Tamagnini, Ione; Puccio, Noemi; Neri, Antonino; Ciarrocchi, Alessia; Fragliasso, Valentina.
  • Tameni A; Laboratory of Translational Research, Azienda USL-IRCCS di Reggio Emilia, Viale Risorgimento 80, 42123, Reggio Emilia, Italy.
  • Mallia S; Laboratory of Translational Research, Azienda USL-IRCCS di Reggio Emilia, Viale Risorgimento 80, 42123, Reggio Emilia, Italy.
  • Manicardi V; Laboratory of Translational Research, Azienda USL-IRCCS di Reggio Emilia, Viale Risorgimento 80, 42123, Reggio Emilia, Italy.
  • Donati B; Laboratory of Translational Research, Azienda USL-IRCCS di Reggio Emilia, Viale Risorgimento 80, 42123, Reggio Emilia, Italy.
  • Torricelli F; Laboratory of Translational Research, Azienda USL-IRCCS di Reggio Emilia, Viale Risorgimento 80, 42123, Reggio Emilia, Italy.
  • Vitale E; Laboratory of Translational Research, Azienda USL-IRCCS di Reggio Emilia, Viale Risorgimento 80, 42123, Reggio Emilia, Italy.
  • Salviato E; Clinical and Experimental Medicine Ph.D. Program, University of Modena and Reggio Emilia, Modena 41125, Italy.
  • Gambarelli G; Laboratory of Translational Research, Azienda USL-IRCCS di Reggio Emilia, Viale Risorgimento 80, 42123, Reggio Emilia, Italy.
  • Muccioli S; Laboratory of Translational Research, Azienda USL-IRCCS di Reggio Emilia, Viale Risorgimento 80, 42123, Reggio Emilia, Italy.
  • Zanelli M; Laboratory of Translational Research, Azienda USL-IRCCS di Reggio Emilia, Viale Risorgimento 80, 42123, Reggio Emilia, Italy.
  • Ascani S; Pathology Unit, Department of Oncology, Azienda Unità Sanitaria Locale - IRCCS di Reggio Emilia, Reggio Emilia, 42123, Italy.
  • Martino G; Pathology Unit, Azienda Ospedaliera Santa Maria di Terni, University of Perugia, 05100 Terni, Italy.
  • Sanguedolce F; Pathology Unit, Azienda Ospedaliera Santa Maria di Terni, University of Perugia, 05100 Terni, Italy.
  • Sauta E; Institute of Hematology and CREO, University of Perugia, Perugia 06129, Italy.
  • Tamagnini I; Pathology Unit, Policlinico Riuniti, University of Foggia, 71122 Foggia, Italy.
  • Puccio N; IRCCS Humanitas Clinical and Research Center, via Manzoni 56, 20089 Rozzano, Milan, Italy.
  • Neri A; Pathology Unit, Department of Oncology, Azienda Unità Sanitaria Locale - IRCCS di Reggio Emilia, Reggio Emilia, 42123, Italy.
  • Ciarrocchi A; Laboratory of Translational Research, Azienda USL-IRCCS di Reggio Emilia, Viale Risorgimento 80, 42123, Reggio Emilia, Italy.
  • Fragliasso V; Scientific Directorate, Azienda USL-IRCCS di Reggio Emilia, Viale Umberto I 50, 42123, Reggio Emilia, Italy.
Nucleic Acids Res ; 52(11): 6171-6182, 2024 Jun 24.
Article en En | MEDLINE | ID: mdl-38597676
ABSTRACT
Chromatin modifiers are emerging as major determinants of many types of cancers, including Anaplastic Large Cell Lymphomas (ALCL), a family of highly heterogeneous T-cell lymphomas for which therapeutic options are still limited. HELLS is a multifunctional chromatin remodeling protein that affects genomic instability by participating in the DNA damage response. Although the transcriptional function of HELLS has been suggested, no clues on how HELLS controls transcription are currently available. In this study, by integrating different multi-omics and functional approaches, we characterized the transcriptional landscape of HELLS in ALCL. We explored the clinical impact of its transcriptional program in a large cohort of 44 patients with ALCL. We demonstrated that HELLS, loaded at the level of intronic regions of target promoters, facilitates RNA Polymerase II (RNAPII) progression along the gene bodies by reducing the persistence of co-transcriptional R-loops and promoting DNA damage resolution. Importantly, selective knockdown of HELLS sensitizes ALCL cells to different chemotherapeutic agents, showing a synergistic effect. Collectively, our work unveils the role of HELLS in acting as a gatekeeper of ALCL genome stability providing a rationale for drug design.
Asunto(s)

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Transcripción Genética / Daño del ADN / ARN Polimerasa II / Estructuras R-Loop Límite: Humans Idioma: En Año: 2024 Tipo del documento: Article

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Transcripción Genética / Daño del ADN / ARN Polimerasa II / Estructuras R-Loop Límite: Humans Idioma: En Año: 2024 Tipo del documento: Article