CDK12: cellular functions and therapeutic potential of versatile player in cancer

Abstract

Cyclin-dependent kinase 12 (CDK12) phosphorylates the C-terminal domain of RNA polymerase II and is needed for the optimal transcription elongation and translation of a subset of human protein-coding genes. The kinase has a pleiotropic effect on the maintenance of genome stability, and its inactivation in prostate and ovarian tumours results in focal tandem duplications, a CDK12-unique genome instability phenotype. CDK12 aberrations were found in many other malignancies and have the potential to be used as biomarkers for therapeutic intervention. Moreover, the inhibition of CDK12 emerges as a promising strategy for treatment in several types of cancers. In this review, we summarize mechanisms that CDK12 utilizes for the regulation of gene expression and discuss how the perturbation of CDK12-sensitive genes contributes to the disruption of cell cycle progression and the onset of genome instability. Furthermore, we describe tumour-suppressive and oncogenic functions of CDK12 and its potential as a biomarker and inhibition target in anti-tumour treatments.

Phase Separation as a Missing Mechanism for Interpretation of Disease Mutations

“…Interestingly, a set of ASD-candidate genes includes specific kinases (CDK13, CCNK, DYRK1A) (Table S1) that may phase separate to capture and phosphorylate the CTD (Lu et al, 2018) and to target RNA Pol II to different condensates. The cancer-associated kinase, CDK12, also phosphorylates RNA Pol II with a potentially similar effect on RNA Pol II partitioning (Bonnal et al, 2020;Pilarova et al, 2020). Given these observations, we expect that ASD-and cancer-associated mutations in IDRs of these kinases (Table S1, S2, S3) could alter their phase separation propensities leading to aberrant localization and phospho-regulation of RNA Pol II.…”

CDK12: A Potent Target and Biomarker for Human Cancer Therapy

“…This may be due to the key role of CDK12 in regulating transcription elongation and the expression of genes involved in DDR, DNA replication and mRNA processing [9,10,12,24]. Abnormal expression or mutation of CDK12 is detected in various cancers, such as breast cancer, ovarian cancer, prostate cancer and gastric cancer [7,15,17,18]. Moreover, CDK12 is also indirectly implicated in esophageal, endometrial, uterine, bladder, colorectal and pancreatic ductal carcinomas [15].…”

“…It complexes with cyclin K to regulate gene transcription elongation via phosphorylating RNA polymerase II (RNAP II) [ 9 , 10 , 11 , 12 , 13 ] and also regulates translation [ 14 ]. Moreover, CDK12 plays a role in RNA splicing, cell cycle progression, cell proliferation, DNA damage response (DDR) and maintenance of genomic stability [ 2 , 9 , 10 , 13 , 14 , 15 , 16 , 17 , 18 ]. Since the mutation or amplification of CDK12 is closely related with tumorigenesis, CDK12 becomes an attractive therapeutic target for cancer treatment [ 7 , 19 , 20 , 21 ].…”

CDK9 activity is critical for maintaining MDM4 overexpression in tumor cells

“…In addition to the regulation of transcription, CDK12 and CDK13 were also reported to modulate alternative splicing of some transcripts, possibly by interactions with RNA processing factors 38,39 . Interestingly, alternative splicing of the MDM4 transcript has been reported as the primary mechanism responsible for MDM4 overexpression in cancer 40 .…”