Role of AF10 in chromatin regulation and cancer
Abstract/Contents
- Abstract
- Histone lysine methylation plays a critical role in gene transcription regulation, cell cycle control, and DNA damage repair. One of the major diseases that histone lysine methylation plays an important role is chromosomal rearrangement mixed lineage leukemia (MLL). In MLL, the H3K4 methyltransferase MLL1 is frequently fused with other protein partners, including AF4, AF9, AF10 and ENL. Studies have found that most of these fusion partners are in complexes with H3K79 methyltransferase Dot1L. Among these proteins, AF10 was identified as a DOT1L cofactor. AF10 is required for H3K79 methylation and cooperates with DOT1L in leukemogenesis. However, the molecular mechanism by which AF10 regulates DOT1L-mediated H3K79 methylation in MLL is not clear. In the first part of this dissertation, I investigate the biochemical, molecular, and cellular roles of AF10 in Dot1L-addicted leukemia. I identified the PHD finger-Zn knuckle-PHD finger (PZP) domain of AF10 as a novel 'reader' that couples unmodified H3K27 recognition to regulate H3K79 methylation. In Chapter 1, I briefly introduce the essence background of histone lysine methylation and its role in biology and human diseases. In Chapter 2, I report the discovery of PZP as a novel histone methylation reader domain. In Chapter 3, I present the solution of AF10PZP crystal structure in H3 binding. In Chapter 4, with reconstitute systems, I establish the role of PZP recognition of H3 in Dot1L function and leukemogenesis in cells. Summarizing in Chapter 5, this work uncover a pivotal role for H3K27 - via readout by the AF10 PZP domain - in regulating the cancer-associated enzyme DOT1L. At the end, I explored the role of non-histone lysine methylation in Chapter 6. I investigate the BAH domains of DNA methyltransferase DNMT1 as a potential lysine methylation reader. I found that KAP1 is heavily methylated in cells, and the first BAH domain of DNMT1 (BAH1) can specifically recognizes both histone H4K20me2 and non-histone protein KAP1 methylation.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2016 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Yang, Ze |
|---|---|
| Associated with | Stanford University, Department of Biology. |
| Primary advisor | Gozani, Or Pinchas |
| Thesis advisor | Gozani, Or Pinchas |
| Thesis advisor | Chua, Katrin Faye |
| Thesis advisor | Morrison, Ashby J |
| Advisor | Chua, Katrin Faye |
| Advisor | Morrison, Ashby J |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Ze Yang. |
|---|---|
| Note | Submitted to the Department of Biology. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2016. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2016 by Ze Yang
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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