ADP-ribosylation of telomeres in human cells

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.