A Cyclin D1 Intrinsically Disordered Domain Accesses Modified Histone Motifs to Govern Gene Transcription

Authors

Xuanmao Jiao
Gabriele Di Sante
Mathew Casimiro
Agnes Tantos
Anthony Ashton, Thomas Jefferson UniversityFollow
Zhiping Li
Yen Quach
Dharmendra Bhargava
Agnese Di Rocco
Claudia Pupo
Marco Crosariol, Thomas Jefferson UniversityFollow
Tamas Lazar
Peter Tompa
Chenguang Wang, Thomas Jefferson UniversityFollow
Zuoren Yu
Zhao Zhang
Kawthar Aldaaysi
Ratna Vadlamudi
Monica Mann
Emmanuel Skordalakes
Andrew Kossenkov
Yanming Du
Richard Pestell

Document Type

Article

Publication Date

1-8-2024

Comments

This article is the author's final published version in Oncogenesis, Volume 13, Issue 1, 2024, Article number 4.

The published version is available at https://doi.org/10.1038/s41389-023-00502-1.

Copyright © The Author(s) 2024.

Abstract

The essential G₁-cyclin, CCND1, is frequently overexpressed in cancer, contributing to tumorigenesis by driving cell-cycle progression. D-type cyclins are rate-limiting regulators of G₁-S progression in mammalian cells via their ability to bind and activate CDK4 and CDK6. In addition, cyclin D1 conveys kinase-independent transcriptional functions of cyclin D1. Here we report that cyclin D1 associates with H2B^S14 via an intrinsically disordered domain (IDD). The same region of cyclin D1 was necessary for the induction of aneuploidy, induction of the DNA damage response, cyclin D1-mediated recruitment into chromatin, and CIN gene transcription. In response to DNA damage H2B^S14 phosphorylation occurs, resulting in co-localization with γH2AX in DNA damage foci. Cyclin D1 ChIP seq and γH2AX ChIP seq revealed ~14% overlap. As the cyclin D1 IDD functioned independently of the CDK activity to drive CIN, the IDD domain may provide a rationale new target to complement CDK-extinction strategies.

Recommended Citation

Jiao, Xuanmao; Di Sante, Gabriele; Casimiro, Mathew; Tantos, Agnes; Ashton, Anthony; Li, Zhiping; Quach, Yen; Bhargava, Dharmendra; Di Rocco, Agnese; Pupo, Claudia; Crosariol, Marco; Lazar, Tamas; Tompa, Peter; Wang, Chenguang; Yu, Zuoren; Zhang, Zhao; Aldaaysi, Kawthar; Vadlamudi, Ratna; Mann, Monica; Skordalakes, Emmanuel; Kossenkov, Andrew; Du, Yanming; and Pestell, Richard, "A Cyclin D1 Intrinsically Disordered Domain Accesses Modified Histone Motifs to Govern Gene Transcription" (2024). Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers. Paper 12.
https://jdc.jefferson.edu/ppcbfp/12

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

Language

English