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Role and regulation of yeast Hrq1 and its human homolog, RECQL4, during DNA crosslink repair

Luong, Thong The (2022) Role and regulation of yeast Hrq1 and its human homolog, RECQL4, during DNA crosslink repair. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Human RECQL4 is a member of the RecQ family of DNA helicases and functions during DNA replication and repair. RECQL4 mutations are associated with developmental defects and cancer. Although RECQL4 mutations lead to disease, RECQL4 overexpression is also observed in cancer, including breast and prostate. Thus, tight regulation of RECQL4 protein levels is crucial for genome stability. Because mammalian RECQL4 is essential, how cells regulate RECQL4 protein levels is largely unknown. Utilizing budding yeast, we investigated the RECQL4 homolog, HRQ1, during DNA crosslink repair. We find that Hrq1 functions to mediate bypass of intrastrand crosslinks. Although Hrq1 is involved in the processing of cisplatin-induced lesions, it is paradoxically degraded by the proteasome following cisplatin treatment. By identifying the targeted lysine residues, we show that preventing Hrq1 degradation results in increased recombination and mutagenesis following cisplatin exposure. Like yeast, human RECQL4 is similarly degraded upon exposure to crosslinking agents and over-expression of RECQL4 results in increased RAD51 foci and mutagenesis. Using bioinformatic approaches, we demonstrate a link between RECQL4 overexpression and good clinical response in cisplatin-treated triple negative breast cancers. Overall, our study uncovers a role for Hrq1/RECQL4 in DNA intrastrand crosslink processing and its protein regulation through proteasomal degradation.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Luong, Thong Thethl27@pitt.eduthl27
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairVan Houten, Bennettbev15@pitt.edubev15
Committee MemberOpresko, Patriciaplo4@pitt.eduplo4
Committee MemberO'Sullivan, Roderick J.rjo@pitt.edurjo
Committee MemberFord, Marijnmarijn@pitt.edumarijn
Thesis AdvisorBernstein, Kara A.karab@pitt.edukarab
Date: 15 June 2022
Date Type: Publication
Defense Date: 13 April 2022
Approval Date: 15 June 2022
Submission Date: 28 April 2022
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 149
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Molecular Pharmacology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: RECQL4, Hrq1, RecQ Helicases, Intrastrand Crosslink, Proteasomal regulation, Recombination, RAD51, Mutation
Date Deposited: 15 Jun 2022 14:02
Last Modified: 15 Jun 2023 05:15

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