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A Study of Structure-Function Relationships of DNA Polymerase Activity on DNA Interstrand Crosslinks

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dc.contributor.advisor Schärer, Orlando D en_US
dc.contributor.advisor Simmerling, Carlos en_US
dc.contributor.author Roy, Upasana en_US
dc.contributor.other Department of Chemistry en_US
dc.date.accessioned 2017-09-20T16:51:47Z
dc.date.available 2017-09-20T16:51:47Z
dc.date.issued 2017-05-01 en_US
dc.identifier.uri http://hdl.handle.net/11401/77050 en_US
dc.description 139 pgs en_US
dc.description.abstract DNA interstrand crosslinks (ICLs) are DNA lesions that covalently link two strands of a DNA duplex, thereby acting as a block to DNA replication and transcription. As a result ICLs are particularly toxic to dividing cells, and ICL-forming agents such as cisplatin, nitrogen mustards and MMC are widely used in cancer chemotherapy. However, there are complex cellular pathways that repair ICLs, contributing to the problem of resistance to these anti-tumor agents. There appear to be multiple ICL repair pathways operating in cells but the majority of ICLs in vertebrates are repaired in a replication-coupled manner. A key step in this repair pathway is the unhooking of the ICL from one of the strands by nucleases, followed by translesion synthesis across the unhooked ICL by DNA polymerases. The structure of the unhooked ICL substrate determines key outcomes such as efficiency and fidelity of the repair process. However the position of incisions by nucleases and the structure of unhooked ICL substrates are not known. Using a strategy developed in our laboratory, I synthesized structurally diverse model unhooked ICLs to investigate the effect of ICL structure on the approach, insertion and extension abilities of replicative and TLS polymerases. I demonstrated that the distortion induced in the duplex by the crosslink, as well as the duplex context of the ICL are important factors that influence the nature of translesion synthesis by DNA polymerases. Surprisingly, I found that the most processed form of an ICLa single crosslinked base that is believed to be a putative intermediate during ICL repaircan be bypassed by replicative polymerases and that ICLs may be repaired without the help of TLS polymerases in some cases. This work provides insight into how structures of unhooked ICLs influence biological outcomes such as occurrence of resistance and secondary tumor formation during the translesion synthesis step in ICL repair. en_US
dc.description.sponsorship This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree. en_US
dc.format Monograph en_US
dc.format.medium Electronic Resource en_US
dc.language.iso en_US en_US
dc.publisher The Graduate School, Stony Brook University: Stony Brook, NY. en_US
dc.subject.lcsh Biochemistry en_US
dc.title A Study of Structure-Function Relationships of DNA Polymerase Activity on DNA Interstrand Crosslinks en_US
dc.type Dissertation en_US
dc.mimetype Application/PDF en_US
dc.contributor.committeemember Sampson, Nicole en_US
dc.contributor.committeemember Simmerling, Carlos en_US
dc.contributor.committeemember Garcia-Diaz, Miguel en_US

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