Senescent cells cluster CTCF on nuclear speckles to instruct an alternative splicing program.

Spiros Palikyras, Vassiliki Varamogiani-Mamatsi, Yajie Zhu, Athanasia Mizi, Shyam Ramasamy, Jonas Viken Grini, Isabel Liebermann, Athanasia Stavropoulou, Andrés Penagos Puig, Tuba Sena Ogurlu-Tank, Konstantinos Kydonakis, Ioanna Papadionysiou, Deniz Bartsch, Yulia Kargapolova, Natalia Rosalia Morero, Konstantinos Sofiadis, Christoforos Nikolaou, Franziska Kundel, Leo Kurian, Jan Ellenberg, A Marieke Oudelaar, Mariano Barbieri, Kai Sandvold Beckwith, Argyris Papantonis

Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany.Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany. · pubmed

Paper

Abstract

Senescence, the endpoint of normal cells' replicative lifespan, is accompanied by a complex sequence of molecular events. One such event is the dramatic reorganization of CTCF into senescence-induced clusters (SICCs). However, the molecular determinants, genomic consequences and functional purpose of SICCs remain unknown. Here we combine three-dimensional genomics, super-resolution imaging, DNA tracing and functional assays with modeling to dissect SICC emergence. We find that, on senescence entry, cells repurpose SRRM2-a key component of nuclear speckles-and BANF1-a 'molecular glue' for chromosomes-to cluster CTCF and rewire genome architecture. This CTCF-centric reorganization in reference to nuclear speckles helps instruct the senescence splicing program, because disruption of SICCs almost fully reverts alternative splicing patterns and delays senescence onset. We therefore uncover a paradigm whereby human cells translate changes in nuclear biochemistry into architectural changes directing splicing choices to commit to the fate of senescence.

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Research summary

Senescent cells repurpose SRRM2 and BANF1 to cluster CTCF on nuclear speckles, thereby instructing an alternative splicing program that drives the commitment to cellular senescence. This paper is relevant because it elucidates a fundamental mechanistic driver of cellular senescence, a key hallmark of aging, by linking nuclear architecture to splicing regulation; however, the impact is limited as it describes a specific molecular pathway within a known aging process rather than offering a novel therapeutic intervention or a paradigm-shifting discovery that bypasses aging.

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