The regulation of p53 function by lysine methylation
Abstract/Contents
- Abstract
- The human p53 tumor suppressor is the most widely studied gene and protein in cellular biology. An open question in the field relates to the regulatory mechanism(s) that manage the complex functions of an essential tumor suppressor protein. Recently, a number of the protein lysine methyltrasferases (PKMTs) that mediate histone lysine methylation have also been identified as having activity on non-histone substrates. Reversible covalent methylation of lysine residues on histone or non-histone proteins constitutes a principal molecular mechanism that guides substrate proteins to diverse biological outcomes. The goal of this work was to 1) expand the understanding of lysine methylation and methyllysine recognition in the context of non-histone tumor suppressor proteins, and 2) elucidate the molecular mechanisms of such events. A handful of studies characterizing lysine methyation events on four distinct lysines in the C-terminal regulatory region of p53, have lead to the emergence of p53 as a model for non-histone lysine methylation. We contributed to this body of work by demonstrating that the lysine methyltransferase enzyme SET8/PR-Set7 is a novel regulator of p53. SET8 monomethylates p53 at lysine 382 (p53K382me1), resulting in reduced transactivation of highly responsive target genes. We used biochemical and crystallographic studies to identify the triple malignant brain tumor (MBT) domain containing chromatin compaction factor L3MBTL1 as the second know p53-effector protein. We demonstrated that SET8-mediated methylation of p53 at K382 promotes the interaction between L3MBTL1 and p53 in cells, and the chromatin occupancy of L3MBTL1 at p53 target promoters, thus providing a molecular explanation for the mechanism by which p53K382me1 is transduced to regulate p53 activity. Additionally we demonstrated that retinoblastomal tumor suppressor (RB) can be mono-methylated in vivo by SMYD2 at lysine 860, and that this methylation provides a direct binding site for L3MBTL1, helping to guide its functions in mammalian cells. In summary, we identified SET8 as a novel p53-modifying enzyme that mediates the regulatory post-translational modification at lysine 382; and, we identified L3MBTL1 a novel methyllysine effector protein for that mark. In a collaborative study we demonstrated that methylation of RB by Smyd2 promotes interaction with L3MBTL1. Together these results suggest that regulation by lysine methylation represents a broader paradigm for modulation of non-histone protein activity.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Copyright date | 2011 |
| Publication date | 2010, c2011; 2010 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | West, Lisandra Elaine |
|---|---|
| Associated with | Stanford University, Department of Biology. |
| Primary advisor | Gozani, Or Pinchas |
| Thesis advisor | Gozani, Or Pinchas |
| Thesis advisor | Chua, Katrin Faye |
| Thesis advisor | Lipsick, Joseph Steven, 1955- |
| Advisor | Chua, Katrin Faye |
| Advisor | Lipsick, Joseph Steven, 1955- |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Lisandra Elaine West. |
|---|---|
| Note | Submitted to the Department of Biology. |
| Thesis | Ph.D. Stanford University 2011 |
| Location | electronic resource |
Access conditions
- Copyright
- © 2011 by Lisandra Elaine West
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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