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Control of telomeric homology-directed repair by poly(ADP-ribose) metabolism

Hoang, My (2020) Control of telomeric homology-directed repair by poly(ADP-ribose) metabolism. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Immediately after single-stranded break (SSB) and double-stranded break (DSB) formation, the synthesis of poly(ADP-ribose) (PAR) reconfigures the local chromatin environment and initiates recruitment of DNA repair proteins. The degradation of PAR chains by poly(ADP-ribose) glycohydrolase (PARG) is essential for DNA repair progression. Here, we show that pharmacological interference of PAR metabolism disrupts the homology-directed repair (HDR) mechanisms that mediate alternative lengthening of telomeres (ALT). Using a proteomics strategy, we uncovered PAR-regulated telomere-associated proteins that coordinate the early stages of the ALT mechanism. These distinct factors exhibit PAR dependency for localization to ALT telomeres in order to orchestrate diverse functions, such as RNA stabilization, actin nucleation, and chromatin remodeling. Most significantly, we identified a key function for PARylation in recruiting the HIRA histone chaperone complex to ALT telomeres, where it is required for deposition of histone H3.3 specifically during G2 Break-Induced Replication (G2-BIR). We propose that HIRA acts to compensate for the loss of a functional ATRX-DAXX complex in ALT cancers and therefore adopts elevated importance in sustaining ALT+ cell viability.

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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Hoang, MyMYH5@pitt.eduMYH5
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairVan Houten, Bennettvanhoutenb@upmc.edu
Thesis AdvisorO'Sullivan, Roderickosullivanr@upmc.edu
Committee MemberOpresko, Patriciaplo4@pitt.eduplo4
Committee MemberBernstein, Karakarab@pitt.edukarab
Committee MemberBerman, Andreaajb190@pitt.eduajb190
Date: 2 January 2020
Date Type: Publication
Defense Date: 4 December 2019
Approval Date: 2 January 2020
Submission Date: 19 December 2019
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 245
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Pharmacology and Chemical Biology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: ALT, HIRA, PARG, PARylation, Telomere
Date Deposited: 03 Jan 2020 04:06
Last Modified: 02 Jan 2021 06:15
URI: http://d-scholarship.pitt.edu/id/eprint/38082

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