OGG1 and MUTYH repair activities promote telomeric 8-oxoguanine induced cellular senescence

Mariarosaria De Rosa; Ryan P Barnes; Prasanth R Nyalapatla; Peter Wipf; Patricia L Opresko

doi:10.1101/2023.04.10.536247

OGG1 and MUTYH repair activities promote telomeric 8-oxoguanine induced cellular senescence

bioRxiv [Preprint]. 2023 Apr 11:2023.04.10.536247. doi: 10.1101/2023.04.10.536247.

Authors

Mariarosaria De Rosa^{1

2}, Ryan P Barnes^{1

2}, Prasanth R Nyalapatla³, Peter Wipf^{2

3}, Patricia L Opresko^{1

2

4}

Affiliations

¹ Department of Environmental and Occupational Health, University of Pittsburgh School of Public Health, Pittsburgh, PA, USA.
² UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
³ Deparment of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA.
⁴ Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Abstract

Telomeres are prone to formation of the common oxidative lesion 8-oxoguanine (8oxoG), and the acute production of 8oxoG damage at telomeres is sufficient to drive rapid cellular senescence. OGG1 and MUTYH glycosylases initiate base excision repair (BER) at 8oxoG sites to remove the lesion or prevent mutation. Here, we show OGG1 loss or inhibition, or MUTYH loss, partially rescues telomeric 8oxoG-induced senescence, and loss of both glycosylases results in a near complete rescue. Loss of these glycosylases also suppresses 8oxoG-induced telomere fragility and dysfunction, indicating that single-stranded break (SSB) intermediates arising downstream of glycosylase activity impair telomere replication. The failure to initiate BER in glycosylase-deficient cells suppresses PARylation at SSB intermediates and confers resistance to the synergistic effects of PARP inhibitors on damage-induced senescence. Our studies reveal that inefficient completion of 8oxoG BER at telomeres triggers cellular senescence via SSB intermediates which impair telomere replication and stability.

Publication types

Preprint