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Regulation of Cell Cycle Transitions...

Branigan, Timothy Bruce.

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Regulation of Cell Cycle Transitions and CHK1 Inhibitor Sensitivity by MMB-FOXM1 Feedback Loops.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Regulation of Cell Cycle Transitions and CHK1 Inhibitor Sensitivity by MMB-FOXM1 Feedback Loops./
作者:	Branigan, Timothy Bruce.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2021,
面頁冊數:	266 p.
附註:	Source: Dissertations Abstracts International, Volume: 83-02, Section: B.
Contained By:	Dissertations Abstracts International83-02B.
標題:	Virology. -
電子資源:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28499109
ISBN:	9798534671278

Regulation of Cell Cycle Transitions and CHK1 Inhibitor Sensitivity by MMB-FOXM1 Feedback Loops.
Branigan, Timothy Bruce.

Regulation of Cell Cycle Transitions and CHK1 Inhibitor Sensitivity by MMB-FOXM1 Feedback Loops. - Ann Arbor : ProQuest Dissertations & Theses, 2021 - 266 p.

Source: Dissertations Abstracts International, Volume: 83-02, Section: B.

Thesis (Ph.D.)--Harvard University, 2021.

This item must not be sold to any third party vendors.

The cell division cycle requires duplication of the genome and segregation of the replicated genomes into daughter cells. Failure to keep these two processes distinct can compromise genomic integrity, causing oncogenic mutations or cell death. The interaction of transcriptional and post-translational pathways coordinates genome duplication and genomes segregation. Post-translationally, cyclin/CDK complexes generate distinct cellular states, while protein degradation erase these states to enable transition to the next. The ATR-CHK1 kinases modulate CDK activity to separate the two cellular states. Transcriptionally, two waves of gene expression facilitate these states: a G1/S wave controlled by E2F to enable DNA replication and a G2/M wave to enable mitosis driven by the MYBL2/MuvB(MMB)-FOXM1 complex.We identified a MYBL2-cyclin F feedback loop controlled by CDK phosphorylation. The E3 ubiquitin ligase complex SKP1-CUL1-F-BOX(SCF)cyclin F specifically degrades MYBL2 in G2/M. Loss of cyclin F led to persistence of the MMB-FOXM1 complex, G2/M gene expression, and cyclin B1 levels through mitosis. A genome-wide CRISPR screen identified the MMB-FOXM1 complex as required for sensitivity to CHK1 inhibitors that induced replication catastrophe. We demonstrated that CHK1i derepressed an MMB-FOXM1-CDK1 positive feedback loop that induced premature mitosis leading to replication stress and cell death.Prolonged CHK1 inhibition led to APC/C dysregulation and CHK1i-induced replication catastrophe. CHK1i induced the APC/C-dependent degradation of origin licensing factors impairing DNA replication. The MMB-FOXM1 complex also was required for impaired DNA replication and loss of origin licensing factors after CHK1 inhibition implicating the mitotic transcriptional program in managing DNA replication. Consequently, the APC/C regulators, Aurora B and FBXO5, were identified as potential biomarkers for CHK1i sensitivity. This work demonstrated how MMB-FOXM1feedback loops facilitated cell cycle transitions that could be dysregulated by CHK1 inhibition.

ISBN: 9798534671278Subjects--Topical Terms:

642304
Virology.
Subjects--Index Terms:

CDK1

Regulation of Cell Cycle Transitions and CHK1 Inhibitor Sensitivity by MMB-FOXM1 Feedback Loops.
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