All Publications


  • Author Correction: R-loop-derived cytoplasmic RNA-DNA hybrids activate an immune response. Nature Crossley, M. P., Song, C., Bocek, M. J., Choi, J. H., Kousouros, J. N., Sathirachinda, A., Lin, C., Brickner, J. R., Bai, G., Lans, H., Vermeulen, W., Abu-Remaileh, M., Cimprich, K. A. 2024

    View details for DOI 10.1038/s41586-024-07064-1

    View details for PubMedID 38263519

  • R-loop-derived cytoplasmic RNA-DNA hybrids activate an immune response. Nature Crossley, M. P., Song, C., Bocek, M. J., Choi, J., Kousorous, J., Sathirachinda, A., Lin, C., Brickner, J. R., Bai, G., Lans, H., Vermeulen, W., Abu-Remaileh, M., Cimprich, K. A. 2022

    Abstract

    R-loops are RNA-DNA-hybrid-containing nucleic acids with important cellular roles. Deregulation of R-loop dynamics can lead to DNA damage and genome instability1, which has been linked to the action of endonucleases such as XPG2-4. However, the mechanisms and cellular consequences of such processing have remained unclear. Here we identify a new population of RNA-DNA hybrids in the cytoplasm that are R-loop-processing products. When nuclear R-loops were perturbed by depleting the RNA-DNA helicase senataxin (SETX) or the breast cancer gene BRCA1(refs. 5-7), we observed XPG- and XPF-dependent cytoplasmic hybrid formation. We identify their source as a subset of stable, overlapping nuclear hybrids with a specific nucleotide signature. Cytoplasmic hybrids bind to the patternrecognition receptors cGAS and TLR3(ref.8), activating IRF3 and inducing apoptosis. Excised hybrids and an R-loop-induced innate immune response were also observed in SETX-mutated cells from patients with ataxia oculomotor apraxia type 2(ref.9) and in BRCA1-mutated cancer cells10. These findings establish RNA-DNA hybrids as immunogenic species that aberrantly accumulate in the cytoplasm after R-loop processing, linking R-loop accumulation to cell death through the innate immune response. Aberrant R-loop processing and subsequent innate immune activation may contribute to many diseases, such as neurodegeneration and cancer.

    View details for DOI 10.1038/s41586-022-05545-9

    View details for PubMedID 36544021

  • HLTF Promotes Fork Reversal, Limiting Replication Stress Resistance and Preventing Multiple Mechanisms of Unrestrained DNA Synthesis. Molecular cell Bai, G. n., Kermi, C. n., Stoy, H. n., Schiltz, C. J., Bacal, J. n., Zaino, A. M., Hadden, M. K., Eichman, B. F., Lopes, M. n., Cimprich, K. A. 2020

    Abstract

    DNA replication stress can stall replication forks, leading to genome instability. DNA damage tolerance pathways assist fork progression, promoting replication fork reversal, translesion DNA synthesis (TLS), and repriming. In the absence of the fork remodeler HLTF, forks fail to slow following replication stress, but underlying mechanisms and cellular consequences remain elusive. Here, we demonstrate that HLTF-deficient cells fail to undergo fork reversal in vivo and rely on the primase-polymerase PRIMPOL for repriming, unrestrained replication, and S phase progression upon limiting nucleotide levels. By contrast, in an HLTF-HIRAN mutant, unrestrained replication relies on the TLS protein REV1. Importantly, HLTF-deficient cells also exhibit reduced double-strand break (DSB) formation and increased survival upon replication stress. Our findings suggest that HLTF promotes fork remodeling, preventing other mechanisms of replication stress tolerance in cancer cells. This remarkable plasticity of the replication fork may determine the outcome of replication stress in terms of genome integrity, tumorigenesis, and response to chemotherapy.

    View details for DOI 10.1016/j.molcel.2020.04.031

    View details for PubMedID 32442397