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 (Unpublished)

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Abstract

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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Details

Item Type:	University of Pittsburgh ETD
Status:	Unpublished
Creators/Authors:	Creators Email Pitt Username ORCID Luong, Thong The thl27@pitt.edu thl27
ETD Committee:	Title Member Email Address Pitt Username ORCID Committee Chair Van Houten, Bennett bev15@pitt.edu bev15 Committee Member Opresko, Patricia plo4@pitt.edu plo4 Committee Member O'Sullivan, Roderick J. rjo@pitt.edu rjo Committee Member Ford, Marijn marijn@pitt.edu marijn Thesis Advisor Bernstein, Kara A. karab@pitt.edu karab
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 2022 14:02
URI:	http://d-scholarship.pitt.edu/id/eprint/42951

Available Versions of this Item

• Role and regulation of yeast Hrq1 and its human homolog, RECQL4, during DNA crosslink repair. (deposited UNSPECIFIED)
  • Role and regulation of yeast Hrq1 and its human homolog, RECQL4, during DNA crosslink repair. (deposited 15 Jun 2022 14:02) [Currently Displayed]

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