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Sullivan, Meghan (2019) FUNCTIONAL INSIGHTS INTO RAD51 REGULATORY PROTEINS IN HOMOLOGOUS RECOMBINATION. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Accurate repair of DNA is critical for genome stability and cancer prevention. DNA double-strand breaks are one of the most toxic lesions and can be repaired using the high-fidelity homologous recombination (HR) pathway. HR is highly conserved and uses a homologous template for repair. One central HR step is RAD51 nucleoprotein filament formation on the single-stranded DNA ends. RAD51 filament formation is required for the homology search and strand invasion steps of HR. RAD51 activity is tightly controlled by many positive and negative regulators, collectively termed the RAD51 mediators. The human RAD51 paralogs (RAD51B, RAD51C, RAD51D, XRCC2, XRCC3, and SWSAP1) are RAD51 mediator proteins that are highly conserved throughout eukaryotes and structurally resemble RAD51.They assemble into subcomplexes, BCDX2, CX3, and the Shu complex,to promote the HR activity of RAD51. The RAD51 mediators function to nucleate, elongate, stabilize, and disassemble RAD51 during repair. RAD51 paralog mutations are found in many breast and ovarian cancers as well as other cancer types. Despite their discovery three decades ago, few advances have been made in understanding their function. This work identified that the C. elegans Shu complex is functionally conserved from yeast and is composed of two RAD-51 paralogs, RFS-1 and RIP-1, which bind SWS-1. Disruption of the worm Shu complex results in DNA damage sensitivity and reduced RAD-51 foci showing for the first time that the Shu complex promotes HR in higher eukaryotes. In subsequent studies in human cell lines,this work demonstrated that disruption of the human RAD51 paralog, RAD51C,through cancer-associated point mutations can also cause DNA damage sensitivity and reduced HR. The conserved Walker A motif of human RAD51C is particularly important for maintaining protein-protein interactions of the BCDX2 and CX3 complexes and maintaining HR proficiency that we propose is critical for prevention of breast and ovarian cancers.Together, this work sheds light onto the function of the RAD51 regulators and their role in maintaining genome stability.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Sullivan, Meghanmrs149@pitt.edumrs149
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee MemberYanowitz, Judith
Committee ChairBernstein, Kara
Committee MemberThomas, Gary
Committee MemberO'Sullivan, Roderick
Committee MemberOpresko, Patricia
Date: 22 January 2019
Date Type: Publication
Defense Date: 29 November 2018
Approval Date: 22 January 2019
Submission Date: 14 January 2019
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 184
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Molecular Genetics and Developmental Biology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: RAD51C, RAD51 paralogs, Homologous Recombination, Ovarian Cancer, Breast Cancer, Shu Complex
Date Deposited: 22 Jan 2019 18:16
Last Modified: 22 Jan 2020 06:15

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