Nucleic acids research, Volume 53, Issue 18, 1 1 2025, Pages gkaf964 Coordinated control of genome-nuclear lamina interactions by topoisomerase 2B and lamin B receptor. van Schaik T, Magnitov M, de Haas M, Breda J, de Wit E, Manjon AG, Medema RH, Gothe HJ, Roukos V, Buckle AJ, Naughton C, Gilbert N, van Steensel B, Manzo SG
Lamina-associated domains (LADs) are megabase-sized genomic regions anchored to the nuclear lamina (NL). Factors controlling the interactions of the genome with the NL have largely remained elusive. Here, we identified DNA topoisomerase 2 beta (TOP2B) as a regulator of these interactions. TOP2B binds predominantly to inter-LAD (iLAD) chromatin and its depletion results in a partial loss of genomic partitioning between LADs and iLADs, suggesting that this enzyme might protect specific iLADs from interacting with the NL. TOP2B depletion affects LAD interactions with lamin B receptor (LBR) more than with lamins. LBR depletion phenocopies the effects of TOP2B depletion, despite the different positioning of the two proteins in the genome. This suggests a complementary mechanism for organizing the genome at the NL. Indeed, co-depletion of TOP2B and LBR causes partial LAD/iLAD inversion, reflecting changes typical of oncogene-induced senescence. We propose that a coordinated axis controlled by TOP2B in iLADs and LBR in LADs maintains the partitioning of the genome between the NL and the nuclear interior.
