Physiological and pathological roles of the transcriptional kinases CDK12 and CDK13 in the central nervous system

IF 13.7 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Cell Death and Differentiation Pub Date : 2024-11-12 DOI:10.1038/s41418-024-01413-3
Consuelo Pitolli, Alberto Marini, Claudio Sette, Vittoria Pagliarini
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Abstract

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.

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转录激酶 CDK12 和 CDK13 在中枢神经系统中的生理和病理作用
细胞周期蛋白依赖性激酶 12(CDK12)和 13(CDK13)控制着基因表达的几个步骤,包括转录、RNA 处理和翻译。CDK12/13 的主要靶标是 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、伸长率和过程活性。CDK12/13 依赖于对 RNAPII 活性的调控,它影响着对所有真核细胞的增殖和活力具有重要功能作用的特定靶基因的表达。由于神经元基因的表达高度依赖于 RNAPII 的活性,CDK12/13 的缺失对神经元细胞的影响尤为明显。CDK12/13 活性的失调会影响神经元前体细胞的干潜能和分化特性,从而对大脑生理产生强烈影响。此外,越来越多的证据也表明 CDK12/13 与脑肿瘤有关。在此,我们将讨论 CDK12 和 CDK13 在基因表达调控中的功能作用,并强调这些高度同源激酶之间的异同,尤其关注它们对大脑生理和病理的影响。最后,我们概述了 CDK12/13 抑制剂及其对脑肿瘤和其他肿瘤性疾病的疗效。
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来源期刊
Cell Death and Differentiation
Cell Death and Differentiation 生物-生化与分子生物学
CiteScore
24.70
自引率
1.60%
发文量
181
审稿时长
3 months
期刊介绍: Mission, vision and values of Cell Death & Differentiation: To devote itself to scientific excellence in the field of cell biology, molecular biology, and biochemistry of cell death and disease. To provide a unified forum for scientists and clinical researchers It is committed to the rapid publication of high quality original papers relating to these subjects, together with topical, usually solicited, reviews, meeting reports, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.
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