Peptide Nucleic Acids (PNAs) are artificial DNA mimics with superior nucleic acid binding capabilities. T7 RNA polymerase (T7 RNAP) transcription upon encountering PNA bound to the non-template DNA strand was studied in vitro. A characteristic pattern of blockage signals was observed, extending downstream from the PNA binding site, similar to that produced by G-rich homopurine-homopyrimidine (hPu-hPy) sequences and likely caused by R-loop formation. Since blocked transcription complexes in association with stable R-loops may interfere with replication and in some cases trigger apoptosis, targeted R-loop formation might be employed to inactivate selected cells, such as those in tumors, based upon their unique complement of expressed genes.
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http://dx.doi.org/10.1002/mc.22209 | DOI Listing |
Inflammation
January 2025
Department of Geriatrics, Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China.
Chronic obstructive pulmonary disease (COPD) is a prevalent chronic inflammatory airway disease with high incidence and significant disease burden. R-loops, functional chromatin structure formed during transcription, are closely associated with inflammation due to its aberrant formation. However, the role of R-loop regulators (RLRs) in COPD remains unclear.
View Article and Find Full Text PDFCell Rep
January 2025
Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China; National Center for Neurological Disorders, Shanghai 200040, China; Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Shanghai 200040, China; Neurosurgical Institute of Fudan University, Shanghai 200040, China; Shanghai Clinical Medical Center of Neurosurgery, Shanghai 200040, China. Electronic address:
Glioblastoma (GBM) is a highly lethal malignant brain tumor with poor survival rates, and chemoresistance poses a significant challenge to the treatment of patients with GBM. Here, we show that transketolase (TKT), a metabolic enzyme in the pentose phosphate pathway (PPP), attenuates the chemotherapy sensitivity of glioma cells in a manner independent of catalytic activity. Mechanistically, chemotherapeutic drugs can facilitate the translocation of TKT protein from the cytosol into the nucleus, where TKT physically interacts with XRN2 to regulate the resolution and removal of R-loops.
View Article and Find Full Text PDFNat Struct Mol Biol
January 2025
Laboratory of Molecular Biophysics, The Rockefeller University, New York, NY, USA.
Following transcript release during intrinsic termination, Escherichia coli RNA polymerase (RNAP) often remains associated with DNA in a post-termination complex (PTC). RNAPs in PTCs are removed from the DNA by the SWI2/SNF2 adenosine triphosphatase (ATPase) RapA. Here we determined PTC structures on negatively supercoiled DNA and with RapA engaged to dislodge the PTC.
View Article and Find Full Text PDFNature
January 2025
Stanford Cancer Institute, School of Medicine, Stanford University, Stanford, CA, USA.
Breast cancer is a highly heterogeneous disease whose prognosis and treatment as defined by the expression of three receptors-oestrogen receptor (ER), progesterone receptor and human epidermal growth factor receptor 2 (HER2; encoded by ERBB2)-is insufficient to capture the full spectrum of clinical outcomes and therapeutic vulnerabilities. Previously, we demonstrated that transcriptional and genomic profiles define eleven integrative subtypes with distinct clinical outcomes, including four ER subtypes with increased risk of relapse decades after diagnosis. Here, to determine whether these subtypes reflect distinct evolutionary histories, interactions with the immune system and pathway dependencies, we established a meta-cohort of 1,828 breast tumours spanning pre-invasive, primary invasive and metastatic disease with whole-genome and transcriptome sequencing.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
January 2025
Program in Genetics, Molecular, and Cellular Biology, Tufts University Graduate School of Biomedical Sciences, Boston, MA 02111.
CAG/CTG repeats are prone to expansion, causing several inherited human diseases. The initiating sources of DNA damage which lead to inaccurate repair of the repeat tract to cause expansions are not fully understood. Expansion-prone CAG/CTG repeats are actively transcribed and prone to forming stable R-loops with hairpin structures forming on the displaced single-stranded DNA (S-loops).
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