Journal article
C16orf72/HAPSTR1/TAPR1 functions with BRCA1/Senataxin to modulate replication-associated R-loops and confer resistance to PARP disruption
- Abstract:
- 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 PARP1/2 gene disruption and identified C16orf72/HAPSTR1/TAPR1 as a novel modulator of replication-associated R-loops. C16orf72 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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 2.5MB, Terms of use)
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- Publisher copy:
- 10.1038/s41467-023-40779-9
Authors
+ Wellcome Trust
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- Funder identifier:
- https://ror.org/029chgv08
- Grant:
- 102348/Z/13/Z
+ Medical Research Council
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- Funder identifier:
- https://ror.org/03x94j517
- Grant:
- MR/P028284/1
- MR/P018963/1
- MR/V00896X/1
- MR/W017350/1
- Publisher:
- Springer Nature
- Journal:
- Nature Communications More from this journal
- Volume:
- 14
- Issue:
- 1
- Article number:
- 5003
- Publication date:
- 2023-09-17
- Acceptance date:
- 2023-08-10
- DOI:
- EISSN:
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2041-1723
- Language:
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English
- Keywords:
- Pubs id:
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1506391
- Local pid:
-
pubs:1506391
- Deposit date:
-
2023-08-10
- ARK identifier:
Terms of use
- Copyright holder:
- Sharma et al.
- Copyright date:
- 2023
- Rights statement:
- © The Author(s) 2023. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
- Notes:
-
This research was funded in whole, or in part, by the Wellcome Trust (Grant 102348/Z/13/Z) and MRC (Grants MR/P028284/1; MR/P018963/1; MR/V00896X/1; MR/W017350/1). For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.
An Author Correction to this article was published on 27 November 2023, see: https://doi.org/10.1038/s41467-023-43353-5
- Licence:
- CC Attribution (CC BY)
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