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

Overview

Journal Oncogenesis

Date 2024 Jan 8

PMID 38191593

Authors

Xuanmao Jiao

Gabriele Di Sante

Mathew C Casimiro

Agnes Tantos

Anthony W Ashton

Zhiping Li

Yen Quach

Dharmendra Bhargava

Agnese Di Rocco

Claudia Pupo

Marco Crosariol

Tamas Lazar

Peter Tompa

Chenguang Wang

Zuoren Yu

Zhao Zhang

Kawthar Aldaaysi

Ratna Vadlamudi

Monica Mann

Emmanuel Skordalakes

Andrew Kossenkov

Yanming Du

Richard G Pestell

Affiliations

Soon will be listed here.

Abstract

The essential G-cyclin, CCND1, is frequently overexpressed in cancer, contributing to tumorigenesis by driving cell-cycle progression. D-type cyclins are rate-limiting regulators of G-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 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 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.

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