CDK9 keeps RNA polymerase II on track

Abstract

Cyclin-dependent kinase 9 (CDK9), the kinase component of positive transcription elongation factor b (P-TEFb), is essential for transcription of most protein-coding genes by RNA polymerase II (RNAPII). By releasing promoter-proximally paused RNAPII into gene bodies, CDK9 controls the entry of RNAPII into productive elongation and is, therefore, critical for efficient synthesis of full-length messenger (m)RNAs. In recent years, new players involved in P-TEFb-dependent processes have been identified and an important function of CDK9 in coordinating elongation with transcription initiation and termination has been unveiled. As the regulatory functions of CDK9 in gene expression continue to expand, a number of human pathologies, including cancers, have been associated with aberrant CDK9 activity, underscoring the need to properly regulate CDK9. Here, I provide an overview of CDK9 function and regulation, with an emphasis on CDK9 dysregulation in human diseases.

Bromodomain and Extra-Terminal Inhibitor BMS-986158 Reverses Latent HIV-1 Infection In Vitro and Ex Vivo by Increasing CDK9 Phosphorylation and Recruitment

“…P-TEFb is a transcription elongation factor consisting of two subunits, i.e., cyclin T1 and CDK9, which play important roles in the transcription of HIV [ 26 ]. The phosphor-CDK9 subunit of P-TEFb promotes HIV-1 transcription elongation via phosphorylation of the carboxyterminal domain (CTD) of RNAP II after recruitment to the HIV-1 LTR by Tat [ 27 ].…”

Transcription Pause and Escape in Neurodevelopmental Disorders

“…CDK9 is widely expressed in all human tissues ( De Luca et al, 1997 ) and plays a role in several diseases, including HIV infection and multiple cancers ( Egloff, 2021 ). In total six patients have been described that carry variants in CDK9 resulting in CHARGE (coloboma, heart defects, atresia choanae, growth retardation, genital abnormalities and ear abnormalities)-like syndrome (OMIM#214800) ( Shaheen et al, 2016 ; Maddirevula et al, 2019 ; Nishina et al, 2021 ).…”

A Review of the Multipronged Attack of Herpes Simplex Virus 1 on the Host Transcriptional Machinery

“…Pausing generally allows for proper recruitment of factors acting later in transcription. In contrast, the release of paused polymerases into productive elongation or premature termination is a major regulatory nexus for viruses like HIV-1 and specific biological processes during development and stress responses [35,36]. The switch from paused to elongating polymerases is typically mediated by positive transcription elongation factor b (P-TEFb), which phosphorylates Pol II, DSIF, and NELF.…”

“…Each immediate-early protein mentioned can affect additional pathways that in turn globally influence transcription factors already regulated by other means. One apparent conflict regarding the loss of promoter-proximal pausing is the fact that HSV inhibits P-TEFb kinase activity, a key facilitator of pause release and whose inhibition globally results in increased polymerase pausing [35,36]. More on this is discussed in the next section.…”

“…As mentioned in the previous section, polymerases are productively released from promoter-proximal pausing due to the kinase subunit of P-TEFb, cyclin-dependent kinase 9 (CDK9), which phosphorylates DSIF, NELF, and Ser2 of the CTD. It is important to note that other Ser2 kinases exist, and blocking CDK9 can also affect their downstream recruitment [36]. Still, activities of these enzymes have not yet been directly explored in HSV infection.…”