人類DNA拓樸異構酶在基因體損傷及穩定性之功能探討

范嘉榕

doi:10.6342/NTU.2008.00316

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人類DNA拓樸異構酶在基因體損傷及穩定性之功能探討

Study on the Roles of Human Topoisomerases in DNA Damage and Chromosome Stability

范嘉榕 , Ph.D　　Advisor：李財坤　　

英文 DOI： 10.6342/NTU.2008.00316

DNA拓樸異構酶DNA損傷反應；蛋白酶體；染色質結構；基因穩定性； DNA topoisomerase ； cleavable complex ； DNA damage response ； proteasome degradation ； chromatin structure ； genome stability

Abstract │ Reference (133)

Abstract 〈TOP〉

Parallel Abstract 〈TOP〉

DNA topoisomerases are ubiquitous, yet magical enzymes that are evolved to solve the topological problems on DNA generated during replication, transcription, recombination and repair. They can relax and/or decatenate DNA by transesterification reaction involving cleavage and religation of DNA phosphodiester bond via active center phosphotyrosyl linkage between DNA and enzyme. In human cells, there are six topoisomerases known to date: nuclear topoisomerase I, topoisomerases IIα and IIβ, topoisomerases IIIα and IIIβ,as well as mitochondria topoisomerase I .The biological roles of many of these members, for example the newly identified topoisomerases IIIα and IIIβ, are still unknown. On the other hand, topoisomerases I and II have been developed as molecular targets of cancer drugs due to their scissoring action on DNA. Nevertheless, many problems remain to be solved regarding the drug selectivity, potency and clinical side effects. In this dissertation, the magic topoisomerase world, including the origin, regulation and maintenance/homeostatic of DNA supercoiling, DNA topoisomerases and their therapeutic implications, is generally reviewed in chapter I. In addition, my studies were intended to expand and offer greater insights into understanding both the bright- and dark-side of this elegant, yet mysterious DNA magician. We uncovered “the roles of human topoisomerase IIIα in chromatin structure and genome stability” in chapter II, which opened up very important aspects about the biological and tumorigenic roles of a young topoisomerase family member. In chapter III, we revealed that “cellular processing pathways contribute to the activation of topoisomerase II-mediated DNA damage responses“. Three cellular activities, replication, transcription and proteasome are required for processing topoisomerase II-linked DNA breakage for initiating downstream DNA damage detection, repair as well as cell death programs. Finally, the conclusion and prospective about this study would be provided in chapter IV.

Reference ( 133 ) 〈TOP〉

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[5] J.C. Wang. Cellular roles of DNA topoisomerases: a molecular perspective, Nat Rev Mol Cell Biol 3 (2002) 430-440.
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