XRN2 interactome reveals its synthetic lethal relationship with PARP1 inhibition
| العنوان: | XRN2 interactome reveals its synthetic lethal relationship with PARP1 inhibition |
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| المؤلفون: | Talysa Viera, Megha Khandelwal, Julio C. Morales, Praveen L. Patidar, Naveen Singh, Edward A. Motea, Farjana J. Fattah |
| المصدر: | Scientific Reports, Vol 10, Iss 1, Pp 1-15 (2020) Scientific Reports |
| بيانات النشر: | Nature Publishing Group, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 0301 basic medicine, Genome instability, DNA Replication, Cell biology, DNA End-Joining Repair, DNA Repair, DNA damage, DNA repair, Molecular biology, Poly (ADP-Ribose) Polymerase-1, lcsh:Medicine, Synthetic lethality, Biology, Genomic Instability, Article, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, PARP1, Humans, DNA Breaks, Double-Stranded, lcsh:Science, Cancer, Multidisciplinary, lcsh:R, RNA, Proliferating cell nuclear antigen, DNA-Binding Proteins, 030104 developmental biology, HEK293 Cells, chemistry, A549 Cells, Exoribonucleases, biology.protein, lcsh:Q, Poly(ADP-ribose) Polymerases, R-Loop Structures, Synthetic Lethal Mutations, 030217 neurology & neurosurgery, DNA, RNA Helicases, DNA Damage, HeLa Cells |
| الوصف: | 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. |
| اللغة: | English |
| تدمد: | 2045-2322 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4c3187fc30b9aadeb8d2fbc859787be0 http://link.springer.com/article/10.1038/s41598-020-71203-7 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....4c3187fc30b9aadeb8d2fbc859787be0 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20452322 |
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