Deregulated DNA ADP-ribosylation impairs telomere replication

• Published in: Nature structural & molecular biology Vol. 31; no. 5; pp. 791 - 800
• Main Authors: Wondisford, Anne R., Lee, Junyeop, Lu, Robert, Schuller, Marion, Groslambert, Josephine, Bhargava, Ragini, Schamus-Haynes, Sandra, Cespedes, Leyneir C., Opresko, Patricia L., Pickett, Hilda A., Min, Jaewon, Ahel, Ivan, O’Sullivan, Roderick J.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.05.2024; Nature Publishing Group
• Subjects: 13/106; 14/32; 14/63; 38/1; 38/71; 631/337/103/560; 631/337/151; 631/337/458/2389; 631/80/103/560; 631/92/458/2389; Adenosine diphosphate; Adenosine Diphosphate Ribose - metabolism; ADP-Ribosylation; Animals; Biochemistry; Biological Microscopy; Biomedical and Life Sciences; Deoxyribonucleic acid; Deregulation; DNA; DNA - metabolism; DNA biosynthesis; DNA Replication; Epigenetics; Fragility; Genomes; Genomic Instability; Humans; Integrity; Life Sciences; Membrane Biology; Mice; Okazaki fragments; Poly (ADP-Ribose) Polymerase-1 - genetics; Poly (ADP-Ribose) Polymerase-1 - metabolism; Poly(ADP-ribose) polymerase; Protein Structure; Replication; Ribose; Single-stranded DNA; Synthesis; Telomerase; Telomere - genetics; Telomere - metabolism; Telomere Shortening; Telomeres; Toxins
• ISSN: 1545-9993; 1545-9985; 1545-9985
• DOI: 10.1038/s41594-024-01279-6

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. Telomeres are endogenous cellular targets of DNA ADP-ribosylation (DNA-ADPr). TARG1-regulated DNA-ADPr is coupled to lagging telomere DNA strand synthesis, and persistent DNA-ADPr, due to TARG1 deficiency, leads to telomere shortening and fragility.