hnRNPUL1 ensures efficient Integrator-mediated cleavage of snRNAs and is mutated in amyotrophic lateral sclerosis

Yonchev, I. D.; Apostol, C. V.; Griffith, L.; Li, A.; Butler, L.; Patrick, H.; Aguilar-Martinez, E.; Whelan, A. G.; Evans, C.; Dickman, M. J.; Cooper-Knock, J.; Shaw, P. J.; West, S.; Barbaric, I.; Sudbery, I. M.; Wilson, S. A.

doi:10.1101/2023.07.22.550030

bioRxiv · 10.1101/2023.07.22.550030

hnRNPUL1 ensures efficient Integrator-mediated cleavage of snRNAs and is mutated in amyotrophic lateral sclerosis

Yonchev, I. D.·Apostol, C. V.·Griffith, L.·Li, A.·Butler, L.·Patrick, H.·Aguilar-Martinez, E.·Whelan, A. G.·Evans, C.·Dickman, M. J.·Cooper-Knock, J.·Shaw, P. J.·West, S.·Barbaric, I.·Sudbery, I. M.·Wilson, S. A.

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Abstract

Integrator cleaves nascent RNA, triggering RNA polymerase II transcription termination, but how cleavage is regulated is poorly understood. Here we show hnRNPUL1 ensures efficient Integrator-mediated cleavage of nascent RNA downstream of snRNA genes and, in the case of U2 snRNA, binds a terminal stem-loop involved in this process. In the nucleoplasm, hnRNPUL1 binds U4 snRNA and SART3 and enables efficient reformation of the U4:U6 di-snRNP for further rounds of pre-mRNA splicing. Sustained hnRNPUL1 loss leads to reduced levels of snRNAs, defects in histone mRNA 3' end processing and loss of Cajal bodies. hnRNPUL1 binds RNA through multiple domains, including a globular central domain comprising tightly juxtaposed SPRY and dead polynucleotide kinase folds. This latter fold allows binding to 5'-monophosphorylated RNAs in a mutually exclusive manner with ATP binding and functions as an XRN2 antagonist when overexpressed. We identify a cohort of amyotrophic lateral sclerosis patients harbouring disruptive mutations in hnRNPUL1. SMN loss in spinal muscular atrophy and hnRNPUL1 loss both disrupt snRNP biogenesis, leading to motor neuron death, suggesting a common aetiology.

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Yonchev, I. D., Apostol, C. V., Griffith, L., Li, A., Butler, L., Patrick, H., Aguilar-Martinez, E., Whelan, A. G., Evans, C., Dickman, M. J., Cooper-Knock, J., Shaw, P. J., West, S., Barbaric, I., Sudbery, I. M., Wilson, S. A.. 2023-07-22. hnRNPUL1 ensures efficient Integrator-mediated cleavage of snRNAs and is mutated in amyotrophic lateral sclerosis. https://doi.org/10.1101/2023.07.22.550030

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