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ADP-ribosylation of telomeres in human cells

Wondisford, Anne Radovick (2024) ADP-ribosylation of telomeres in human cells. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

The recognition that DNA can be ADP-ribosylated has major consequences for our understanding of how ADP-ribosylation (ADPr) contributes to genome stability, epigenetics, and immunity. Yet, whether DNA-ADP-ribosylation (DNA-ADPr) contributes to genome stability and how it is regulated currently remains unknown. Here, we show that telomeres are subject to DNA-ADPr which is catalyzed by PARP1 and removed by TARG1. Mechanistically, we show that DNA-ADPr is coupled to lagging telomere DNA strand synthesis, forming at single-stranded DNA present at unligated Okazaki fragments and on the 3’ single-stranded telomere overhang. Ultimately, persistent DNA-ADPr due to TARG1 deficiency leads to telomere shortening. Furthermore, utilizing the bacterial DNA-ADP-ribosyltransferase (DarT) toxin to directly target DNA-ADPr at telomeres, we demonstrate that unhydrolyzed DNA-ADPr compromises telomere replication and telomere integrity. Thus, by identifying telomeres as chromosomal targets of DNA-ADPr whose deregulation compromises telomere replication and integrity, our study provides fundamental knowledge of the critical importance of controlling DNA-ADP ribosylation turnover for sustained genome stability.

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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Wondisford, Anne Radovickarw90@pitt.eduarw90
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairNeumann, Carola
Committee MemberVan Houten, Bennett
Committee MemberOpresko, Patricia
Committee MemberSinghi, Aatur
Thesis AdvisorO'Sullivan, Roderick
Date: 27 September 2024
Date Type: Publication
Defense Date: 21 November 2023
Approval Date: 27 September 2024
Submission Date: 18 April 2024
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 164
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: cancer biology, PARP1, ADP-ribosylation, telomeres, alternative lengthening of telomeres, TARG1
Date Deposited: 27 Sep 2024 15:30
Last Modified: 27 Sep 2024 15:30
URI: http://d-scholarship.pitt.edu/id/eprint/46065

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