Investigation of cell-cycle entry and DNA replication termination using single-cell microscopy
Abstract/Contents
- Abstract
- The cell cycle is a highly orchestrated series of cellular events that results in the duplication of DNA and division into two daughter cells. As a critical process during tissue development and homeostasis, the cell cycle is tightly regulated at the cellular, tissue, and organismal levels. In this thesis, we study two cellular processes that are key to cell-cycle regulation: the decision to enter the cell cycle in response to extracellular signals, and the multi-step process that replicates DNA. In the first study, we find that the decision of a newborn cell to proliferate or become quiescent is controlled by the memory of local cell density that is inherited from its mother cell. This memory regulates the expression of the cell-cycle activator cyclin D1 and inhibitor p27. Cyclin D1 and p27 form an activator-inhibitor balance in newborn cells that regulates the proliferation-quiescence decision in a sharp, ultrasensitive manner. We further show that competing cell density and mitogen signals are funneled into the cyclin D1-p27 balance through ERK signaling. We propose that memory of cell density, coupled to tight regulation of proliferation by the activator- inhibitor balance, may contribute to robust control of cell density and tissue homeostasis. In the second study, we demonstrate that replisome disassembly, a final step during DNA replication that is generally thought to be functionally downstream of nascent DNA synthesis, is continuously required for efficient DNA synthesis. Failure to disassemble replisomes traps essential replisome components on chromatin, which prevents their recycling into the soluble pool and blocks replication initiation. Cells with defects in replisome disassembly experience slow and incomplete DNA replication, G2/M checkpoint activation, and cell-cycle arrest. We also show that LRR1, which encodes a key component of the E3 ligase CRL2-LRR1 that initiates replisome disassembly, is an essential gene in actively dividing human cells. Thus we propose that inhibiting CRL2-LRR1 activity may be a potential target for cancer therapy, which acts by blocking the recycling of key replication factors that are in high demand in cancer cells due to the higher replicative activity in many cancers.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2021; ©2021 |
| Publication date | 2021; 2021 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Fan, Yilin, (Researcher in chemical and systems biology) |
|---|---|
| Degree supervisor | Ferrell, James E |
| Degree supervisor | Meyer, Tobias |
| Thesis advisor | Ferrell, James E |
| Thesis advisor | Meyer, Tobias |
| Thesis advisor | Brandman, Onn |
| Thesis advisor | Wysocka, Joanna, Ph. D. |
| Degree committee member | Brandman, Onn |
| Degree committee member | Wysocka, Joanna, Ph. D. |
| Associated with | Stanford University, Department of Chemical and Systems Biology |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Yilin Fan. |
|---|---|
| Note | Submitted to the Department of Chemical and Systems Biology. |
| Thesis | Thesis Ph.D. Stanford University 2021. |
| Location | https://purl.stanford.edu/zm982wf9873 |
Access conditions
- Copyright
- © 2021 by Yilin Fan
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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