Deregulated DNA ADP-ribosylation impairs telomere replication

  • Nat Struct Mol Biol. 2024 May;31(5):791-800. doi: 10.1038/s41594-024-01279-6.
Anne R Wondisford  1 ,  Junyeop Lee  #  2 ,  Robert Lu  #  3 ,  Marion Schuller  4 ,  Josephine Groslambert  4 ,  Ragini Bhargava  1 ,  Sandra Schamus-Haynes  1 ,  Leyneir C Cespedes  2 ,  Patricia L Opresko  1  5 ,  Hilda A Pickett  3 ,  Jaewon Min  2 ,  Ivan Ahel  4 ,  Roderick J O'Sullivan  6
Affiliations
  • 1. Department of Pharmacology and Chemical Biology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA.
  • 2. Institute for Cancer Genetics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.
  • 3. Telomere Length Regulation Unit, Children's Medical Research Institute, Faculty of Medicine and Health, University of Sydney, Westmead, New South Wales, Australia.
  • 4. Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
  • 5. Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA.
  • 6. Department of Pharmacology and Chemical Biology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA. [email protected].
  • # Contributed equally.
PMID: 38714889 DOI: 10.1038/s41594-024-01279-6
Abstract

The recognition that DNA can be ADP ribosylated provides an unexpected regulatory level of how ADP-ribosylation contributes to genome stability, Epigenetics and immunity. Yet, it remains unknown whether DNA ADP-ribosylation (DNA-ADPr) promotes genome stability and how it is regulated. Here, we show that telomeres are subject to DNA-ADPr 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. Persistent DNA-linked ADPr, due to TARG1 deficiency, eventually leads to telomere shortening. Furthermore, using the Bacterial DNA ADP-ribosyl-transferase toxin to modify DNA at telomeres directly, we demonstrate that unhydrolyzed DNA-linked ADP-ribose compromises telomere replication and telomere integrity. Thus, by identifying telomeres as chromosomal targets of PARP1 and TARG1-regulated DNA-ADPr, whose deregulation compromises telomere replication and integrity, our study highlights and establishes the critical importance of controlling DNA-ADPr turnover for sustained genome stability.

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