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XRN2 interactome reveals its synthetic lethal relationship with PARP1 inhibition
Persistent R-loops (RNA–DNA hybrids with a displaced single-stranded DNA) create DNA damage and lead to genomic instability. The 5′-3′-exoribonuclease 2 (XRN2) degrades RNA to resolve R-loops and promotes transcription termination. Previously, XRN2 was implicated in DNA double strand break (DSB) rep...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455564/ https://www.ncbi.nlm.nih.gov/pubmed/32859985 http://dx.doi.org/10.1038/s41598-020-71203-7 |
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author | Patidar, Praveen L. Viera, Talysa Morales, Julio C. Singh, Naveen Motea, Edward A. Khandelwal, Megha Fattah, Farjana J. |
author_facet | Patidar, Praveen L. Viera, Talysa Morales, Julio C. Singh, Naveen Motea, Edward A. Khandelwal, Megha Fattah, Farjana J. |
author_sort | Patidar, Praveen L. |
collection | PubMed |
description | Persistent R-loops (RNA–DNA hybrids with a displaced single-stranded DNA) create DNA damage and lead to genomic instability. The 5′-3′-exoribonuclease 2 (XRN2) degrades RNA to resolve R-loops and promotes transcription termination. Previously, XRN2 was implicated in DNA double strand break (DSB) repair and in resolving replication stress. Here, using tandem affinity purification-mass spectrometry, bioinformatics, and biochemical approaches, we found that XRN2 associates with proteins involved in DNA repair/replication (Ku70-Ku80, DNA-PKcs, PARP1, MCM2-7, PCNA, RPA1) and RNA metabolism (RNA helicases, PRP19, p54(nrb), splicing factors). Novel major pathways linked to XRN2 include cell cycle control of chromosomal replication and DSB repair by non-homologous end joining. Investigating the biological implications of these interactions led us to discover that XRN2 depletion compromised cell survival after additional knockdown of specific DNA repair proteins, including PARP1. XRN2-deficient cells also showed enhanced PARP1 activity. Consistent with concurrent depletion of XRN2 and PARP1 promoting cell death, XRN2-deficient fibroblast and lung cancer cells also demonstrated sensitivity to PARP1 inhibition. XRN2 alterations (mutations, copy number/expression changes) are frequent in cancers. Thus, PARP1 inhibition could target cancers exhibiting XRN2 functional loss. Collectively, our data suggest XRN2’s association with novel protein partners and unravel synthetic lethality between XRN2 depletion and PARP1 inhibition. |
format | Online Article Text |
id | pubmed-7455564 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-74555642020-09-01 XRN2 interactome reveals its synthetic lethal relationship with PARP1 inhibition Patidar, Praveen L. Viera, Talysa Morales, Julio C. Singh, Naveen Motea, Edward A. Khandelwal, Megha Fattah, Farjana J. Sci Rep Article Persistent R-loops (RNA–DNA hybrids with a displaced single-stranded DNA) create DNA damage and lead to genomic instability. The 5′-3′-exoribonuclease 2 (XRN2) degrades RNA to resolve R-loops and promotes transcription termination. Previously, XRN2 was implicated in DNA double strand break (DSB) repair and in resolving replication stress. Here, using tandem affinity purification-mass spectrometry, bioinformatics, and biochemical approaches, we found that XRN2 associates with proteins involved in DNA repair/replication (Ku70-Ku80, DNA-PKcs, PARP1, MCM2-7, PCNA, RPA1) and RNA metabolism (RNA helicases, PRP19, p54(nrb), splicing factors). Novel major pathways linked to XRN2 include cell cycle control of chromosomal replication and DSB repair by non-homologous end joining. Investigating the biological implications of these interactions led us to discover that XRN2 depletion compromised cell survival after additional knockdown of specific DNA repair proteins, including PARP1. XRN2-deficient cells also showed enhanced PARP1 activity. Consistent with concurrent depletion of XRN2 and PARP1 promoting cell death, XRN2-deficient fibroblast and lung cancer cells also demonstrated sensitivity to PARP1 inhibition. XRN2 alterations (mutations, copy number/expression changes) are frequent in cancers. Thus, PARP1 inhibition could target cancers exhibiting XRN2 functional loss. Collectively, our data suggest XRN2’s association with novel protein partners and unravel synthetic lethality between XRN2 depletion and PARP1 inhibition. Nature Publishing Group UK 2020-08-28 /pmc/articles/PMC7455564/ /pubmed/32859985 http://dx.doi.org/10.1038/s41598-020-71203-7 Text en © The Author(s) 2020 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. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Patidar, Praveen L. Viera, Talysa Morales, Julio C. Singh, Naveen Motea, Edward A. Khandelwal, Megha Fattah, Farjana J. XRN2 interactome reveals its synthetic lethal relationship with PARP1 inhibition |
title | XRN2 interactome reveals its synthetic lethal relationship with PARP1 inhibition |
title_full | XRN2 interactome reveals its synthetic lethal relationship with PARP1 inhibition |
title_fullStr | XRN2 interactome reveals its synthetic lethal relationship with PARP1 inhibition |
title_full_unstemmed | XRN2 interactome reveals its synthetic lethal relationship with PARP1 inhibition |
title_short | XRN2 interactome reveals its synthetic lethal relationship with PARP1 inhibition |
title_sort | xrn2 interactome reveals its synthetic lethal relationship with parp1 inhibition |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455564/ https://www.ncbi.nlm.nih.gov/pubmed/32859985 http://dx.doi.org/10.1038/s41598-020-71203-7 |
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