Distinct Cdk9-phosphatase switches act at the beginning and end of elongation by RNA polymerase II

Pabitra K. Parua, Sampada Kalan, Bradley Benjamin, Miriam Sansó and Robert P. Fisher ()
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Pabitra K. Parua: Icahn School of Medicine at Mount Sinai
Sampada Kalan: Icahn School of Medicine at Mount Sinai
Bradley Benjamin: Icahn School of Medicine at Mount Sinai
Miriam Sansó: Icahn School of Medicine at Mount Sinai
Robert P. Fisher: Icahn School of Medicine at Mount Sinai

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: Abstract Reversible phosphorylation of Pol II and accessory factors helps order the transcription cycle. Here, we define two kinase-phosphatase switches that operate at different points in human transcription. Cdk9/cyclin T1 (P-TEFb) catalyzes inhibitory phosphorylation of PP1 and PP4 complexes that localize to 3′ and 5′ ends of genes, respectively, and have overlapping but distinct specificities for Cdk9-dependent phosphorylations of Spt5, a factor instrumental in promoter-proximal pausing and elongation-rate control. PP1 dephosphorylates an Spt5 carboxy-terminal repeat (CTR), but not Spt5-Ser666, a site between Kyrpides-Ouzounis-Woese (KOW) motifs 4 and 5, whereas PP4 can target both sites. In vivo, Spt5-CTR phosphorylation decreases as transcription complexes pass the cleavage and polyadenylation signal (CPS) and increases upon PP1 depletion, consistent with a PP1 function in termination first uncovered in yeast. Depletion of PP4-complex subunits increases phosphorylation of both Ser666 and the CTR, and promotes redistribution of promoter-proximally paused Pol II into gene bodies. These results suggest that switches comprising Cdk9 and either PP4 or PP1 govern pause release and the elongation-termination transition, respectively.

Date: 2020
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DOI: 10.1038/s41467-020-18173-6

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