OGG1 and MUTYH repair activities promote telomeric 8-oxoguanine induced senescence in human fibroblasts
Abstract Telomeres are hypersensitive to the formation of the common oxidative lesion 8-oxoguanine (8oxoG), which impacts telomere stability and function. OGG1 and MUTYH glycosylases initiate base excision repair (BER) to remove 8oxoG or prevent mutation. Here, we show OGG1 loss or inhibition, or MU...
Saved in:
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-01-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55638-4 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832585573611601920 |
|---|---|
| author | Mariarosaria De Rosa Ryan P. Barnes Ariana C. Detwiler Prasanth R. Nyalapatla Peter Wipf Patricia L. Opresko |
| author_facet | Mariarosaria De Rosa Ryan P. Barnes Ariana C. Detwiler Prasanth R. Nyalapatla Peter Wipf Patricia L. Opresko |
| author_sort | Mariarosaria De Rosa |
| collection | DOAJ |
| description | Abstract Telomeres are hypersensitive to the formation of the common oxidative lesion 8-oxoguanine (8oxoG), which impacts telomere stability and function. OGG1 and MUTYH glycosylases initiate base excision repair (BER) to remove 8oxoG or prevent mutation. Here, we show OGG1 loss or inhibition, or MUTYH loss, partially rescues telomeric 8oxoG-induced premature senescence and associated proinflammatory responses, while loss of both glycosylases causes a near complete rescue in human fibroblasts. Glycosylase deficiency also suppresses 8oxoG-induced telomere fragility and dysfunction, indicating that downstream single-stranded break (SSB) repair intermediates impair telomere replication. Preventing BER initiation suppresses PARylation and confers resistance to the synergistic effects of PARP inhibitors on 8oxoG-induced senescence. However, OGG1 activity is essential for preserving cell growth after chronic telomeric 8oxoG formation, whereas MUTYH promotes senescence to prevent chromosomal instability from unrepaired damage. Our studies reveal that inefficient completion of 8oxoG BER at telomeres triggers cellular senescence via SSB intermediates which disrupt telomere function. |
| format | Article |
| id | doaj-art-75651e9879124ddab47e1d6925997ebe |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-75651e9879124ddab47e1d6925997ebe2025-01-26T12:42:15ZengNature PortfolioNature Communications2041-17232025-01-0116111810.1038/s41467-024-55638-4OGG1 and MUTYH repair activities promote telomeric 8-oxoguanine induced senescence in human fibroblastsMariarosaria De Rosa0Ryan P. Barnes1Ariana C. Detwiler2Prasanth R. Nyalapatla3Peter Wipf4Patricia L. Opresko5UPMC Hillman Cancer Center at the University of PittsburghUPMC Hillman Cancer Center at the University of PittsburghUPMC Hillman Cancer Center at the University of PittsburghDepartment of Chemistry, University of PittsburghUPMC Hillman Cancer Center at the University of PittsburghUPMC Hillman Cancer Center at the University of PittsburghAbstract Telomeres are hypersensitive to the formation of the common oxidative lesion 8-oxoguanine (8oxoG), which impacts telomere stability and function. OGG1 and MUTYH glycosylases initiate base excision repair (BER) to remove 8oxoG or prevent mutation. Here, we show OGG1 loss or inhibition, or MUTYH loss, partially rescues telomeric 8oxoG-induced premature senescence and associated proinflammatory responses, while loss of both glycosylases causes a near complete rescue in human fibroblasts. Glycosylase deficiency also suppresses 8oxoG-induced telomere fragility and dysfunction, indicating that downstream single-stranded break (SSB) repair intermediates impair telomere replication. Preventing BER initiation suppresses PARylation and confers resistance to the synergistic effects of PARP inhibitors on 8oxoG-induced senescence. However, OGG1 activity is essential for preserving cell growth after chronic telomeric 8oxoG formation, whereas MUTYH promotes senescence to prevent chromosomal instability from unrepaired damage. Our studies reveal that inefficient completion of 8oxoG BER at telomeres triggers cellular senescence via SSB intermediates which disrupt telomere function.https://doi.org/10.1038/s41467-024-55638-4 |
| spellingShingle | Mariarosaria De Rosa Ryan P. Barnes Ariana C. Detwiler Prasanth R. Nyalapatla Peter Wipf Patricia L. Opresko OGG1 and MUTYH repair activities promote telomeric 8-oxoguanine induced senescence in human fibroblasts Nature Communications |
| title | OGG1 and MUTYH repair activities promote telomeric 8-oxoguanine induced senescence in human fibroblasts |
| title_full | OGG1 and MUTYH repair activities promote telomeric 8-oxoguanine induced senescence in human fibroblasts |
| title_fullStr | OGG1 and MUTYH repair activities promote telomeric 8-oxoguanine induced senescence in human fibroblasts |
| title_full_unstemmed | OGG1 and MUTYH repair activities promote telomeric 8-oxoguanine induced senescence in human fibroblasts |
| title_short | OGG1 and MUTYH repair activities promote telomeric 8-oxoguanine induced senescence in human fibroblasts |
| title_sort | ogg1 and mutyh repair activities promote telomeric 8 oxoguanine induced senescence in human fibroblasts |
| url | https://doi.org/10.1038/s41467-024-55638-4 |
| work_keys_str_mv | AT mariarosariaderosa ogg1andmutyhrepairactivitiespromotetelomeric8oxoguanineinducedsenescenceinhumanfibroblasts AT ryanpbarnes ogg1andmutyhrepairactivitiespromotetelomeric8oxoguanineinducedsenescenceinhumanfibroblasts AT arianacdetwiler ogg1andmutyhrepairactivitiespromotetelomeric8oxoguanineinducedsenescenceinhumanfibroblasts AT prasanthrnyalapatla ogg1andmutyhrepairactivitiespromotetelomeric8oxoguanineinducedsenescenceinhumanfibroblasts AT peterwipf ogg1andmutyhrepairactivitiespromotetelomeric8oxoguanineinducedsenescenceinhumanfibroblasts AT patricialopresko ogg1andmutyhrepairactivitiespromotetelomeric8oxoguanineinducedsenescenceinhumanfibroblasts |