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） 控制基因表达的几个步骤，包括转录、RNA 加工和翻译。CDK12/13 的主要靶点是 RNA 聚合酶 II （RNAPII） 羧基末端结构域的丝氨酸 2 残基，从而影响酶的方向性、延伸速率和持续合成能力。RNAPII 活性的 CDK12/13 依赖性调节影响所选靶基因的表达，这些靶基因在所有真核细胞的增殖和活力中具有重要功能作用。神经元细胞特别容易受到 CDK12/13 丢失的影响，这是由于神经元基因对其表达的 RNAPII 持续合成能力的高度依赖性。CDK12/13 活性的失调通过影响神经元前体细胞的干性电位和分化特性，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。在本文中，我们讨论了 CDK12 和 CDK13 在基因表达调控中的功能作用，并强调了这些高度同源激酶之间的相似性和差异性，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疾病中的疗效。