The HELLS–MCM5 axis coordinates transcription–replication dynamics to preserve genomic integrity in ALK-negative anaplastic large cell lymphoma
5 affiliations
- 1Laboratory of Translational Research, Azienda USL-IRCCS di Reggio Emilia , Viale Risorgimento 80, 42123 Reggio Emilia ,
- 2Clinical and Experimental Medicine PhD Programme, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia , Modena 41125 ,
- 3Molecular and Regenerative Medicine PhD Program, Department of Life Sciences, University of Modena and Reggio Emilia , Modena 41125 ,
- 4Pathology Unit, Department of Oncology, Azienda Unità Sanitaria Locale - IRCCS di Reggio Emilia , Reggio Emilia 42123 ,
- 5Scientific Directorate, Azienda USL-IRCCS di Reggio Emilia , Viale Umberto I 50, 42123 Reggio Emilia ,
Abstract
The chromatin remodeler HELLS acts as a pleiotropic guardian of genomic integrity, orchestrating critical processes from DNA replication to DNA damage repair. In anaplastic large cell lymphoma (ALCL), HELLS functions as a transcriptional sentinel, fine-tuning chromatin accessibility and RNA polymerase II kinetics to sustain the oncogenic transcriptional landscape essential for lymphomagenesis. Here we show that HELLS preserves genomic stability and sustains ALK-negative ALCL proliferation by preventing transcription–replication conflicts. HELLS acts as a global regulator of R-loop homeostasis while transcriptionally sustaining MCM5, a core subunit of the replicative MCM2–7 complex, which locally restrains replication-transcription collisions at actively transcribed loci. Mechanistically, HELLS loss reduces MCM5 levels, triggering aberrant firing of origins within transcriptionally active regions and consequent collisions between replication forks and the transcription machinery. Being positioned distally from R-loop-enriched sites, HELLS and MCM5 cooperate to preserve genome integrity, with MCM5 acting as the effector that delivers locus-specific protection against replication-associated genomic instability. Pharmacological or genetic disruption of this axis increases R-loop burden and drastically reduces the survival of ALK-negative ALCL cells, providing a rationale for combination therapy. Collectively, the HELLS–MCM5 module emerges as a master coordinator of transcription–replication dynamics and a novel therapeutic vulnerability in aggressive lymphomas.
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BibTeX
@article{mallia2026hellsmcm5,
title = {{The HELLS–MCM5 axis coordinates transcription–replication dynamics to preserve genomic integrity in ALK-negative anaplastic large cell lymphoma}},
author = {Selene Mallia and Giulia Gambarelli and Emanuele Vitale and Veronica Manicardi and Elisa Salviato and Pierluigi Di Chiaro and Rebecca Vezzani and Benedetta Donati and Federica Torricelli and Magda Zanelli and Annalisa Tameni and Ione Tamagnini and Noemi Puccio and Antonino Neri and Alessia Ciarrocchi and Valentina Fragliasso},
journal = {Nucleic Acids Research},
year = {2026},
month = oct,
doi = {10.1093/nar/gkag1023},
url = {https://academic.oup.com/nar/article/doi/10.1093/nar/gkag1023/9005088},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - The HELLS–MCM5 axis coordinates transcription–replication dynamics to preserve genomic integrity in ALK-negative anaplastic large cell lymphoma
AU - Selene Mallia
AU - Giulia Gambarelli
AU - Emanuele Vitale
AU - Veronica Manicardi
AU - Elisa Salviato
AU - Pierluigi Di Chiaro
AU - Rebecca Vezzani
AU - Benedetta Donati
AU - Federica Torricelli
AU - Magda Zanelli
AU - Annalisa Tameni
AU - Ione Tamagnini
AU - Noemi Puccio
AU - Antonino Neri
AU - Alessia Ciarrocchi
AU - Valentina Fragliasso
PY - 2026
DA - 2026/10/01
JO - Nucleic Acids Research
DO - 10.1093/nar/gkag1023
UR - https://academic.oup.com/nar/article/doi/10.1093/nar/gkag1023/9005088
AB - The chromatin remodeler HELLS acts as a pleiotropic guardian of genomic integrity, orchestrating critical processes from DNA replication to DNA damage repair. In anaplastic large cell lymphoma (ALCL), HELLS functions as a transcriptional sentinel, fine-tuning chromatin accessibility and RNA polymerase II kinetics to sustain the oncogenic transcriptional landscape essential for lymphomagenesis. Here we show that HELLS preserves genomic stability and sustains ALK-negative ALCL proliferation by preventing transcription–replication conflicts. HELLS acts as a global regulator of R-loop homeostasis while transcriptionally sustaining MCM5, a core subunit of the replicative MCM2–7 complex, which locally restrains replication-transcription collisions at actively transcribed loci. Mechanistically, HELLS loss reduces MCM5 levels, triggering aberrant firing of origins within transcriptionally active regions and consequent collisions between replication forks and the transcription machinery. Being positioned distally from R-loop-enriched sites, HELLS and MCM5 cooperate to preserve genome integrity, with MCM5 acting as the effector that delivers locus-specific protection against replication-associated genomic instability. Pharmacological or genetic disruption of this axis increases R-loop burden and drastically reduces the survival of ALK-negative ALCL cells, providing a rationale for combination therapy. Collectively, the HELLS–MCM5 module emerges as a master coordinator of transcription–replication dynamics and a novel therapeutic vulnerability in aggressive lymphomas.
SN - 0305-1048
SN - 1362-4962
ER -