SUMO2 Promotes Histone Pre-mRNA Processing by Stabilizing Histone Locus Body Interactions and Facilitating U7 snRNP Assembly

He, S.; Lyu, P.; Skinner, M. W.; Desotell, A.; Foley, B.; McCaig, C. M.; Wang, W.; Qian, J.; Tong, L.; Marzluff, W. F.; Matunis, M. J.

doi:10.1101/2025.02.15.638447

bioRxiv · 10.1101/2025.02.15.638447

SUMO2 Promotes Histone Pre-mRNA Processing by Stabilizing Histone Locus Body Interactions and Facilitating U7 snRNP Assembly

He, S.·Lyu, P.·Skinner, M. W.·Desotell, A.·Foley, B.·McCaig, C. M.·Wang, W.·Qian, J.·Tong, L.·Marzluff, W. F.·Matunis, M. J.

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Abstract

Histone mRNAs are the only non-polyadenylated mRNAs in eukaryotic cells and require specialized processing in the histone locus body (HLB), a nuclear body where essential processing factors, including the U7 snRNP, are concentrated. Recent studies have revealed that misregulation of histone pre-mRNA processing can lead to polyadenylation of histone mRNAs and disruption of histone protein homeostasis. Despite links to human disease, the factors contributing to polyadenylation of histone mRNAs and the mechanisms underlying HLB assembly and U7 snRNP biogenesis remain unclear. Here, we report novel functions of the small ubiquitin-related modifier 2 (SUMO2) in promoting histone pre-mRNA processing. Using a SUMO2 knockout osteosarcoma cell line, we identified a defect in 3 end cleavage and a global increase in histone mRNA polyadenylation. Subsequent analysis of HLBs revealed increased dynamics and reduced levels of the U7 snRNP complex. By over-expressing U7 snRNP-specific components, Lsm11 and U7 snRNA, we rescued U7 snRNP levels and processing defects in SUMO2 knockout cells. Through analysis of Lsm11, we identified a SUMO-interacting motif in its N-terminus required for efficient formation of U7 snRNP. Collectively, we demonstrate that SUMO2 promotes histone pre-mRNA 3 end processing by stabilizing HLB interactions and facilitating U7 snRNP assembly.

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He, S., Lyu, P., Skinner, M. W., Desotell, A., Foley, B., McCaig, C. M., Wang, W., Qian, J., Tong, L., Marzluff, W. F., Matunis, M. J.. 2025-02-18. SUMO2 Promotes Histone Pre-mRNA Processing by Stabilizing Histone Locus Body Interactions and Facilitating U7 snRNP Assembly. https://doi.org/10.1101/2025.02.15.638447

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