C16orf72/HAPSTR1/TAPR1 functions with BRCA1/Senataxin to modulate replication-associated R-loops and confer resistance to PARP disruption
While the toxicity of PARP inhibitors to cells with defects in homologous recombination (HR) is well established, other synthetic lethal interactions with PARP1/PARP2 disruption are poorly defined. To inform on these mechanisms we conducted a genome-wide screen for genes that are synthetic lethal wi...
| Main Authors: | , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Springer Nature
2023
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| _version_ | 1797110722429190144 |
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| author | Sharma, A Ramlee, MK Kosmin, J Wolstenholme, A Ronson, G Jones, D Ebner, D Shamkhi, N Sims, D Gibbs-Seymour, I Lakin, N |
| author_facet | Sharma, A Ramlee, MK Kosmin, J Wolstenholme, A Ronson, G Jones, D Ebner, D Shamkhi, N Sims, D Gibbs-Seymour, I Lakin, N |
| author_sort | Sharma, A |
| collection | OXFORD |
| description | While the toxicity of PARP inhibitors to cells with defects in homologous recombination (HR) is well established, other synthetic lethal interactions with PARP1/PARP2 disruption are poorly defined. To inform on these mechanisms we conducted a genome-wide screen for genes that are synthetic lethal with <i>PARP1/2</i> gene disruption and identified <i>C16orf72/HAPSTR1/TAPR1</i> as a novel modulator of replication-associated R-loops. <i>C16orf72</i> is critical to facilitate replication fork restart, suppress DNA damage and maintain genome stability in response to replication stress. Importantly, C16orf72 and PARP1/2 function in parallel pathways to suppress DNA:RNA hybrids that accumulate at stalled replication forks. Mechanistically, this is achieved through an interaction of C16orf72 with BRCA1 and the RNA/DNA helicase Senataxin to facilitate their recruitment to RNA:DNA hybrids and confer resistance to PARP inhibitors. Together, this identifies a C16orf72/Senataxin/BRCA1-dependent pathway to suppress replication-associated R-loop accumulation, maintain genome stability and confer resistance to PARP inhibitors. |
| first_indexed | 2024-03-07T07:58:49Z |
| format | Journal article |
| id | oxford-uuid:4dd5a0c1-a940-47d8-a0bf-26213801281c |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:58:49Z |
| publishDate | 2023 |
| publisher | Springer Nature |
| record_format | dspace |
| spelling | oxford-uuid:4dd5a0c1-a940-47d8-a0bf-26213801281c2023-09-07T09:05:15ZC16orf72/HAPSTR1/TAPR1 functions with BRCA1/Senataxin to modulate replication-associated R-loops and confer resistance to PARP disruptionJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:4dd5a0c1-a940-47d8-a0bf-26213801281cEnglishSymplectic ElementsSpringer Nature2023Sharma, ARamlee, MKKosmin, JWolstenholme, ARonson, GJones, DEbner, DShamkhi, NSims, DGibbs-Seymour, ILakin, NWhile the toxicity of PARP inhibitors to cells with defects in homologous recombination (HR) is well established, other synthetic lethal interactions with PARP1/PARP2 disruption are poorly defined. To inform on these mechanisms we conducted a genome-wide screen for genes that are synthetic lethal with <i>PARP1/2</i> gene disruption and identified <i>C16orf72/HAPSTR1/TAPR1</i> as a novel modulator of replication-associated R-loops. <i>C16orf72</i> is critical to facilitate replication fork restart, suppress DNA damage and maintain genome stability in response to replication stress. Importantly, C16orf72 and PARP1/2 function in parallel pathways to suppress DNA:RNA hybrids that accumulate at stalled replication forks. Mechanistically, this is achieved through an interaction of C16orf72 with BRCA1 and the RNA/DNA helicase Senataxin to facilitate their recruitment to RNA:DNA hybrids and confer resistance to PARP inhibitors. Together, this identifies a C16orf72/Senataxin/BRCA1-dependent pathway to suppress replication-associated R-loop accumulation, maintain genome stability and confer resistance to PARP inhibitors. |
| spellingShingle | Sharma, A Ramlee, MK Kosmin, J Wolstenholme, A Ronson, G Jones, D Ebner, D Shamkhi, N Sims, D Gibbs-Seymour, I Lakin, N C16orf72/HAPSTR1/TAPR1 functions with BRCA1/Senataxin to modulate replication-associated R-loops and confer resistance to PARP disruption |
| title | C16orf72/HAPSTR1/TAPR1 functions with BRCA1/Senataxin to modulate replication-associated R-loops and confer resistance to PARP disruption |
| title_full | C16orf72/HAPSTR1/TAPR1 functions with BRCA1/Senataxin to modulate replication-associated R-loops and confer resistance to PARP disruption |
| title_fullStr | C16orf72/HAPSTR1/TAPR1 functions with BRCA1/Senataxin to modulate replication-associated R-loops and confer resistance to PARP disruption |
| title_full_unstemmed | C16orf72/HAPSTR1/TAPR1 functions with BRCA1/Senataxin to modulate replication-associated R-loops and confer resistance to PARP disruption |
| title_short | C16orf72/HAPSTR1/TAPR1 functions with BRCA1/Senataxin to modulate replication-associated R-loops and confer resistance to PARP disruption |
| title_sort | c16orf72 hapstr1 tapr1 functions with brca1 senataxin to modulate replication associated r loops and confer resistance to parp disruption |
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