Abstract/Details

Emerging roles for the double strand break repair protein 53BP1 in transcriptional regulation


2008 2008

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Abstract (summary)

Disruption of the mechanisms that regulate cell-cycle checkpoints, DNA repair, and apoptosis results in genomic instability and often leads to the development of cancer. In response to double stranded breaks (DSBs) as induced by ionizing radiation (IR), generated during DNA replication, or through immunoglobulin heavy chain (IgH) rearrangements in T and B cells of lymphoid origin, the protein kinases ATM and ATR are central players that activate signaling pathways leading to DSB repair. p53 binding protein 1 (53BP1) participates in the repair of DNA double stranded breaks (DSBs) where it is recruited to or near sites of DNA damage. In addition to its well established role in DSB repair, multiple lines of evidence implicate 53BP1 in transcription which stem from its initial discovery as a p53 binding protein in a yeast two-hybrid screen. However, the mechanisms behind the role of 53BP1 in these processes are not well understood.

53BP1 possesses several motifs that are likely important for its role in DSB repair including two BRCA1 C-terminal repeats, tandem Tudor domains, and a variety of phosphorylation sites. In addition to these motifs, we identified a glycine and arginine rich region (GAR) upstream of the Tudor domains, a sequence that is oftentimes serves as a site for protein arginine methylation. The focus of this project was to characterize the methylation of 53BP1 and to evaluate how methylation influenced the role of 53BP1 as a tumor suppressor.

Using a variety of biochemical techniques, we demonstrated that 53BP1 is methylated by the PRMT1 methyltransferase in vivo. Moreover, GAR methylation occurs on arginine residues in an asymmetric manner. We further show that sequences upstream of the Tudor domains that do not include the GAR stretch are sufficient for 53BP1 oligomerization in vivo. While investigating the role of arginine methylation in 53BP1 function, we discovered that 53BP1 associates with proteins of the general transcription apparatus as well as to other factors implicated in coordinating transcription with chromatin function. Collectively, these data support a role for 53BP1 in regulating transcription and provide insight into the possible mechanisms by which this occurs.

Indexing (details)


Subject
Molecular biology;
Biochemistry
Classification
0307: Molecular biology
0487: Biochemistry
Identifier / keyword
Pure sciences; Biological sciences; 53BP1; DNA damage; Double-strand break repair; Transcription; Tumor suppressor
Title
Emerging roles for the double strand break repair protein 53BP1 in transcriptional regulation
Author
Adams, Melissa Marie
Number of pages
112
Publication year
2008
Degree date
2008
School code
2034
Source
DAI-B 69/07, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
ISBN
9780549735960
Advisor
Carpenter, Phillip B.
University/institution
The University of Texas Graduate School of Biomedical Sciences at Houston
University location
United States -- Texas
Degree
Ph.D.
Source type
Dissertations & Theses
Language
English
Document type
Dissertation/Thesis
Dissertation/thesis number
3322426
ProQuest document ID
304840445
Copyright
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
http://search.proquest.com/docview/304840445
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