Disruption of CDK7 signaling leads to catastrophic chromosomal instability coupled with a loss of condensin-mediated chromatin compaction

Chromatin organization is highly dynamic and modulates DNA replication, transcription, and chromosome segregation. Condensin is essential for chromosome assembly during mitosis and meiosis, as well as maintenance of chromosome structure during interphase. While it is well established that sustained...

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Published in:	The Journal of biological chemistry Vol. 299; no. 7; p. 104834
Main Authors:	Piemonte, Katrina M., Webb, Bryan M., Bobbitt, Jessica R., Majmudar, Parth R., Cuellar-Vite, Leslie, Bryson, Benjamin L., Latina, Nicholas C., Seachrist, Darcie D., Keri, Ruth A.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01-07-2023 American Society for Biochemistry and Molecular Biology
Subjects:	CDK7 Chromatin - genetics chromosomal instability Chromosomes - genetics condensin CT7001 cyclin dependent kinase 7 Cyclin-Dependent Kinases - genetics Meiosis Mitosis mitotic catastrophe SMC2 THZ1 TNBC triple negative breast cancer condensin EFC CT7001 CDK RNA Pol II CDK7i SMC2 BSA DSB SE mitotic catastrophe chromosomal instability TNBC SCLC cyclin dependent kinase 7 GO CIN HCC mitosis THZ1 CAK CDK7 Hi-C TAD ChIP-seq triple negative breast cancer
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Summary:	Chromatin organization is highly dynamic and modulates DNA replication, transcription, and chromosome segregation. Condensin is essential for chromosome assembly during mitosis and meiosis, as well as maintenance of chromosome structure during interphase. While it is well established that sustained condensin expression is necessary to ensure chromosome stability, the mechanisms that control its expression are not yet known. Herein, we report that disruption of cyclin-dependent kinase 7 (CDK7), the core catalytic subunit of CDK-activating kinase, leads to reduced transcription of several condensin subunits, including structural maintenance of chromosomes 2 (SMC2). Live and static microscopy revealed that inhibiting CDK7 signaling prolongs mitosis and induces chromatin bridge formation, DNA double-strand breaks, and abnormal nuclear features, all of which are indicative of mitotic catastrophe and chromosome instability. Affirming the importance of condensin regulation by CDK7, genetic suppression of the expression of SMC2, a core subunit of this complex, phenocopies CDK7 inhibition. Moreover, analysis of genome-wide chromatin conformation using Hi-C revealed that sustained activity of CDK7 is necessary to maintain chromatin sublooping, a function that is ascribed to condensin. Notably, the regulation of condensin subunit gene expression is independent of superenhancers. Together, these studies reveal a new role for CDK7 in sustaining chromatin configuration by ensuring the expression of condensin genes, including SMC2.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work.
ISSN:	0021-9258 1083-351X
DOI:	10.1016/j.jbc.2023.104834