Pitolli Consuelo, Marini Alberto, Sette Claudio, Pagliarini Vittoria
Department of Neuroscience, Section of Human Anatomy, Catholic University of the Sacred Heart, 00168, Rome, Italy.
GSTEP-Organoids Research Core Facility, IRCCS Fondazione Policlinico Universitario Agostino Gemelli, 00168, Rome, Italy.
Cell Death Differ. 2025 Mar;32(3):371-381. doi: 10.1038/s41418-024-01413-3. Epub 2024 Nov 12.
The cyclin-dependent kinases 12 (CDK12) and 13 (CDK13) govern several steps of gene expression, including transcription, RNA processing and translation. The main target of CDK12/13 is the serine 2 residue of the carboxy-terminal domain of RNA polymerase II (RNAPII), thus influencing the directionality, elongation rate and processivity of the enzyme. The CDK12/13-dependent regulation of RNAPII activity influences the expression of selected target genes with important functional roles in the proliferation and viability of all eukaryotic cells. Neuronal cells are particularly affected by the loss of CDK12/13, as result of the high dependency of neuronal genes on RNAPII processivity for their expression. Deregulation of CDK12/13 activity strongly affects brain physiology by influencing the stemness potential and differentiation properties of neuronal precursor cells. Moreover, mounting evidence also suggest the involvement of CDK12/13 in brain tumours. Herein, we discuss the functional role(s) of CDK12 and CDK13 in gene expression regulation and highlight similarities and differences between these highly homologous kinases, with particular attention to their impact on brain physiology and pathology. Lastly, we provide an overview of CDK12/13 inhibitors and of their efficacy in brain tumours and other neoplastic diseases.
细胞周期蛋白依赖性激酶12（CDK12）和13（CDK13）调控基因表达的多个步骤，包括转录、RNA加工和翻译。CDK12/13的主要作用靶点是RNA聚合酶II（RNAPII）羧基末端结构域的丝氨酸2残基，从而影响该酶的方向性、延伸速率和持续合成能力。CDK12/13对RNAPII活性的依赖性调控影响特定靶基因的表达，这些靶基因在所有真核细胞的增殖和存活中发挥重要功能作用。神经元细胞尤其受CDK12/13缺失的影响，因为神经元基因的表达高度依赖于RNAPII的持续合成能力。CDK12/13活性失调通过影响神经元前体细胞的干性潜能和分化特性，强烈影响脑生理学。此外，越来越多的证据还表明CDK12/13与脑肿瘤有关。在此，我们讨论CDK12和CDK13在基因表达调控中的功能作用，强调这两种高度同源激酶之间的异同，特别关注它们对脑生理学和病理学的影响。最后，我们概述了CDK12/13抑制剂及其在脑肿瘤和其他肿瘤性疾病中的疗效。
