A cyclin D1 intrinsically disordered domain accesses modified histone motifs to govern gene transcription

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

doi:10.1038/s41389-023-00502-1

A cyclin D1 intrinsically disordered domain accesses modified histone motifs to govern gene transcription

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 SkordalakesAndrew Kossenkov, Yanming Du, Richard G. Pestell

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Article number	4
Journal	Oncogenesis
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41389-023-00502-1
State	Published - Dec 2024

ASJC Scopus subject areas

Molecular Biology
Cancer Research

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Jiao, X., Di Sante, G., Casimiro, M. C., Tantos, A., Ashton, A. W., Li, Z., Quach, Y., Bhargava, D., Di Rocco, A., Pupo, C., Crosariol, M., Lazar, T., Tompa, P., Wang, C., Yu, Z., Zhang, Z., Aldaaysi, K., Vadlamudi, R., Mann, M., ... Pestell, R. G. (2024). A cyclin D1 intrinsically disordered domain accesses modified histone motifs to govern gene transcription. Oncogenesis, 13(1), Article 4. https://doi.org/10.1038/s41389-023-00502-1

Jiao, X, Di Sante, G, Casimiro, MC, Tantos, A, Ashton, AW, Li, Z, Quach, Y, Bhargava, D, Di Rocco, A, Pupo, C, Crosariol, M, Lazar, T, Tompa, P, Wang, C, Yu, Z, Zhang, Z, Aldaaysi, K, Vadlamudi, R, Mann, M, Skordalakes, E, Kossenkov, A, Du, Y & Pestell, RG 2024, 'A cyclin D1 intrinsically disordered domain accesses modified histone motifs to govern gene transcription', Oncogenesis, vol. 13, no. 1, 4. https://doi.org/10.1038/s41389-023-00502-1

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title = "A cyclin D1 intrinsically disordered domain accesses modified histone motifs to govern gene transcription",

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 H2BS14 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 H2BS14 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.",

author = "Xuanmao Jiao and {Di Sante}, Gabriele and Casimiro, {Mathew C.} and Agnes Tantos and Ashton, {Anthony W.} and Zhiping Li and Yen Quach and Dharmendra Bhargava and {Di Rocco}, Agnese and Claudia Pupo and Marco Crosariol and Tamas Lazar and Peter Tompa and Chenguang Wang and Zuoren Yu and Zhao Zhang and Kawthar Aldaaysi and Ratna Vadlamudi and Monica Mann and Emmanuel Skordalakes and Andrew Kossenkov and Yanming Du and Pestell, {Richard G.}",

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month = dec,

doi = "10.1038/s41389-023-00502-1",

language = "English (US)",

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AU - Jiao, Xuanmao

AU - Di Sante, Gabriele

AU - Casimiro, Mathew C.

AU - Tantos, Agnes

AU - Ashton, Anthony W.

AU - Li, Zhiping

AU - Quach, Yen

AU - Bhargava, Dharmendra

AU - Di Rocco, Agnese

AU - Pupo, Claudia

AU - Crosariol, Marco

AU - Lazar, Tamas

AU - Tompa, Peter

AU - Wang, Chenguang

AU - Yu, Zuoren

AU - Zhang, Zhao

AU - Aldaaysi, Kawthar

AU - Vadlamudi, Ratna

AU - Mann, Monica

AU - Skordalakes, Emmanuel

AU - Kossenkov, Andrew

AU - Du, Yanming

AU - Pestell, Richard G.

PY - 2024/12

Y1 - 2024/12

N2 - 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 H2BS14 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 H2BS14 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.

AB - 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 H2BS14 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 H2BS14 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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A cyclin D1 intrinsically disordered domain accesses modified histone motifs to govern gene transcription

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