Genetic inactivation of Cdk7 leads to cell cycle arrest and induces premature aging due to adult stem cell exhaustion

Abstract

Cyclin‐dependent kinase (Cdk)7, the catalytic subunit of the Cdk‐activating kinase (CAK) complex has been implicated in the control of cell cycle progression and of RNA polymerase II (RNA pol II)‐mediated transcription. Genetic inactivation of the Cdk7 locus revealed that whereas Cdk7 is completely dispensable for global transcription, is essential for the cell cycle via phosphorylation of Cdk1 and Cdk2. In vivo, Cdk7 is also indispensable for cell proliferation except during the initial stages of embryonic development. Interestingly, widespread elimination of Cdk7 in adult tissues with low proliferative indexes had no phenotypic consequences. However, ablation of conditional Cdk7 alleles in tissues with elevated cellular turnover led to the efficient repopulation of these tissues with Cdk7‐expressing cells most likely derived from adult stem cells that may have escaped the inactivation of their targeted Cdk7 alleles. This process, a physiological attempt to maintain tissue homeostasis, led to the attrition of adult stem cell pools and to the appearance of age‐related phenotypes, including telomere shortening and early death.

The arginylation branch of the N-end rule pathway positively regulates cellular autophagic flux and clearance of proteotoxic proteins

“…5C). MDC1 and CDK7, both sensing DNA damage and replication stress, 60,61 were also upregulated after PCA treatment, while those of proteasome subunits and stable proteins, such as PSMA4, ADRM1, and ACTB were unchanged (Fig. 5C).…”

Cdks, cyclins and CKIs: roles beyond cell cycle regulation

“…A better understanding of how Cdk/cyclin complexes trigger each transition and how the CTD code is deciphered into productive events during RNA synthesis will be the aim of future investigations. Unlike cell cycle regulation, which is plagued by extensive compensatory mechanisms, Cdk and cyclin members involved in transcriptional control appear to be non-redundant as their ablation usually results in embryonic lethality; this applies to Cdk7 (Ganuza et al, 2012), Cdk8 (Westerling et al, 2007), Cdk11 (Li et al, 2004), cyclin H (Patel and Simon, 2010), cyclin T2 (Kohoutek et al, 2009) and cyclin K (Blazek et al, 2011).…”

Hallmarks of the ageing lung

“…In particular, in high-turnover organs a constant asymmetric division and differentiation of stem cells is proposed to maintain tissue homeostasis and self-renewal. Over time and age, however, the demand for stem cells appears to exceed the supply provided by stem cell niches [106][107][108]. The lung is a slow-turnover organ [109]; however, evidence concerning human lung tissue turnover is sparse to date.…”