5/Huge thanks to my amazing colleagues in the @opreskolab.bsky.social , @barneslab.bsky.social , @adetwiler.bsky.social , our collaborators Peter Wipf and Prasanth Nyalapatla. We dedicate this manuscript to the late Marcel Bruchez who initially developed the FAP and was an exceptional collaborator.

4/ Importantly, we uncovered a novel role for MUTYH: beyond preventing mutagenesis (as long known), MUTYH also promotes senescence, safeguarding the genome from instability caused by accumulation of unrepaired telomeric 8oxoG.

3/ However, under chronic oxidative damage at telomeres, OGG1 is essential for long-term cell growth, whereas MUTYH promotes senescence. Without MUTYH, cells escape senescence but face increased genomic instability – a dangerous trade-off.

1/ We selectively generated 8oxoG at telomeres in human fibroblasts deficient in either OGG1, MUTYH, or both glycosylases.These cells respectively showed a partial or near complete rescue of multiple hallmarks of acute telomeric 8oxoG-induced senescence, including proinflammatory responses.

3/ However, under chronic oxidative damage at telomeres, OGG1 is essential for long-term cell growth, whereas MUTYH promotes senescence. Without MUTYH, cells escape senescence but face increased genomic instability – a dangerous trade-off.

2/ The problem was the repair intermediates accumulated following OGG1 and MUTYH repair activity: these cause PARylation at telomeres, replication stress and DNA damage response activation. This triggers p53-mediated senescence, exacerbated by the synergistic effect of PARP inhibitor Olaparib.

1/ We selectively generated 8oxoG at telomeres in human fibroblasts deficient in either OGG1, MUTYH, or both glycosylases.These cells respectively showed a partial or near complete rescue of multiple hallmarks of acute telomeric 8oxoG-induced senescence, including proinflammatory responses.