| Autor: |
Patidar PL; Department of Chemistry, New Mexico Institute of Mining and Technology, 801 Leroy Pl., Socorro, NM, 87801, USA. Praveen.Patidar@nmt.edu., Viera T; Department of Chemistry, New Mexico Institute of Mining and Technology, 801 Leroy Pl., Socorro, NM, 87801, USA., Morales JC; Department of Neurosurgery, University of Oklahoma Health Science Center, Oklahoma City, OK, 73104, USA., Singh N; Department of Biochemistry and Molecular Biology, Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, 46202, USA., Motea EA; Department of Biochemistry and Molecular Biology, Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, 46202, USA., Khandelwal M; Department of Chemistry, New Mexico Institute of Mining and Technology, 801 Leroy Pl., Socorro, NM, 87801, USA., Fattah FJ; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA. |
| Abstrakt: |
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. |
