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MOLECULAR MECHANISMS OF RECURRENT CHROMOSOMAL
REARRANGEMENTS IN HUMAN LEUKEMIAS AND LYMPHOMAS
by
Albert G Tsai
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(BIOCHEMISTRY AND MOLECULAR BIOLOGY)
August 2008
Copyright 2008 Albert G Tsai
Object Description
| Title | Molecular mechanisms of recurrent chromosomal translocations in human leukemias and lymphomas |
| Author | Tsai, Albert G. |
| Author email | albertts@usc.edu |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Biochemistry & Molecular Biology |
| School | Keck School of Medicine |
| Date defended/completed | 2008-06-05 |
| Date submitted | 2008 |
| Restricted until | Unrestricted |
| Date published | 2008-07-21 |
| Advisor (committee chair) | Lieber, Michael R. |
| Advisor (committee member) |
Hsieh, Chih-Lin Haworth, Ian S. Hacia, Joseph G. Wang, Clay C. |
| Abstract | The bcl-2 translocation, t(14;18)(q32;q21), is found in about 50% of all non-Hodgkin 's lymphomas, and the bcl-1 translocation, t(11;14)(q13;q32), in >90% of mantle cell lymphomas, making them the most common chromosomal rearrangements in human lymphoma. They occur when double-strand breaks on the bcl-2 region, 18q21, or the bcl-1 region, 11q13, are joined to those from an ongoing V(D)J recombination event on 14q32 via the nonhomologous end joining (NHEJ) pathway. While the V(D)J and NHEJ processes have been extensively characterized, the nature of double-strand breakage at the bcl-1 and bcl-2 regions has remained a mystery since their discovery almost 25 years ago. Computational statistical analysis of more than 1,700 breakpoints from human lymphoid and myeloid chromosomal rearrangements yields an intriguing finding: Translocations occurring at the pro-B/pre-B stage, including the bcl-1 and bcl-2 translocations, are highly focused to the dinucleotide sequence CpG. In addition to the bcl-1 major translocation cluster (MTC), the bcl-2 major breakpoint region (MBR), the bcl-2 intermediate cluster region (icr), and the bcl-2 minor cluster region (mcr), CpG hotspots also occur at the E2A cluster region from t(1;19)(q23;p13) E2A-PBX1 translocations. We do not see such hotspots in rearrangements in lymphoid-myeloid progenitors, mature B cells, or T cells, including t(12;21)(p12;q22) TEL-AML1, t(8;21)(q22;q22) AML1-ETO, t(9;22)(q34;q11) BCR-ABL, t(8;14)(q24;q32), c-myc-IgH switch, and del(1)(p32) SCL-SIL, just to name a few. Furthermore, we demonstrate a unique breakpoint distribution around CpGs, consistent with the structure-specific endonuclease activity of the lymphoid-specific RAG complex acting on bubble, mismatch, and gap DNA substrates.; CpG is of special significance in vertebrates because of the tendency for cytosines in this context to be methylated at the C5 position, and deaminated to another endogenous base, thymine. Theresulting T:G mismatches are not always repaired, leading to a genome-wide CpG depletion over evolutionary time termed "CpG suppression" as well as high rates of mutations at CpGs in tumor suppressor genes in many cancers. However, CpG has not previously been described as a motif for chromosomal translocation. We propose a lesion-specific double-strand breakage mechanism involving the RAG complex acting at deaminated methyl-CpGs to explain the observed stage-specificity and unique breakpoint distributions at these cluster regions. |
| Keyword | chromosomal translocation; chromosomal rearrangement; DNA double-strand break repair; non-Hodgkin's lymphoma |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Type | texts |
| Legacy record ID | usctheses-m1365 |
| Rights | Tsai, Albert G. |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | http://www.usc.edu/isd/libraries/services/ask_a_librarian/email/ |
| Filename | etd-Tsai-20080721 |
| Archival file | uscthesesreloadpub_Volume23/etd-Tsai-20080721.pdf |
Description
| Title | Page 1 |
| Full text | MOLECULAR MECHANISMS OF RECURRENT CHROMOSOMAL REARRANGEMENTS IN HUMAN LEUKEMIAS AND LYMPHOMAS by Albert G Tsai A Dissertation Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (BIOCHEMISTRY AND MOLECULAR BIOLOGY) August 2008 Copyright 2008 Albert G Tsai |
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