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Combinatorial control of Spo11 alternative splicing by modulation of RNA polymerase II dynamics and splicing factor recruitment during meiosis.
Cell Death & Disease ( IF 8.1 ) Pub Date : 2020-04-17 , DOI: 10.1038/s41419-020-2443-y
Eleonora Cesari 1, 2 , Maria Loiarro 2 , Chiara Naro 1, 2 , Marco Pieraccioli 2 , Donatella Farini 2, 3 , Livia Pellegrini 2, 3 , Vittoria Pagliarini 1, 2 , Pamela Bielli 2, 3 , Claudio Sette 1, 2
Affiliation  

Homologous recombination and chromosome segregation in meiosis rely on the timely expression of two splice variants of the endonuclease SPO11, named α and β, which respectively skip or include exon 2. However, in spite of its physiological importance, the mechanism underlying Spo11 alternative splicing in meiosis is still unknown. By screening the activity of factors that are predicted to bind the alternatively spliced region of Spo11, we identified hnRNPH as a key regulator of SPO11α splicing in mouse spermatocytes. Although hnRNPH was not upregulated in meiosis concomitantly with the switch in splicing, its recruitment to Spo11 pre-mRNA was favored by selective modulation of RNA polymerase II (RNAPII) phosphorylation and processivity in proximity of exon 2. The hnRNPH binding sites were localized near those of splicing factors that promote SPO11β splicing, suggesting that hnRNPH favors exon 2 skipping by competing out positive regulators. Indeed, hnRNPH binds proximal to a consensus motif for Sam68, a positive regulator of SPO11β splicing in vitro and in vivo, and it interferes with Sam68 binding to the Spo11 pre-mRNA. Thus, our work reveals that modulation of RNAPII dynamics in concert with hnRNPH recruitment exerts a combinatorial control of the timely regulated Spo11 splicing during meiosis.

中文翻译:

通过减数分裂过程中RNA聚合酶II动力学和剪接因子募集的调节来控制Spo11选择性剪接。

减数分裂中的同源重组和染色体分离依赖于核酸内切酶SPO11的两个剪接变体的及时表达,命名为α和β,它们分别跳过或包含外显子2。但是,尽管其具有生理重要性,但Spo11选择性剪接的机制减数分裂仍然未知。通过筛选预计结合Spo11的可变剪接区域的因子的活性,我们确定hnRNPH是小鼠精母细胞中SPO11α剪接的关键调控因子。尽管在剪接过程中hnRNPH并未在减数分裂中被上调,但选择性调节RNA聚合酶II(RNAPII)的磷酸化和在外显子2附近的持续性有利于hnRNPH向Spo11 pre-mRNA的募集。hnRNPH结合位点位于促进SPO11β剪接的剪接因子附近,表明hnRNPH通过竞争阳性调节子而有利于跳过外显子2。实际上,hnRNPH与Sam68(在体外和体内剪接的SPO11β的阳性调节子)的共有基序相结合,并且干扰Sam68与Spo11 pre-mRNA的结合。因此,我们的工作表明,与hnRNPH募集相协调的RNAPII动态调节对减数分裂过程中及时调节的Spo11剪接产生了组合控制。
更新日期:2020-04-24
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