CSL controls telomere maintenance and genome stability in human dermal fibroblasts.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 31467287.
- Also identified by DOI 10.1038/s41467-019-11785-7 and PMC identifier 6715699.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Genomic instability is a hallmark of cancer. Whether it also occurs in Cancer Associated Fibroblasts (CAFs) remains to be carefully investigated. Loss of CSL/RBP-Jκ, the effector of canonical NOTCH signaling with intrinsic transcription repressive function, causes conversion of dermal fibroblasts into CAFs. Here, we find that CSL down-modulation triggers DNA damage, telomere loss and chromosome end fusions that also occur in skin Squamous Cell Carcinoma (SCC)-associated CAFs, in which CSL is decreased. Separately from its role in transcription, we show that CSL is part of a multiprotein telomere protective complex, binding directly and with high affinity to telomeric DNA as well as to UPF1 and Ku70/Ku80 proteins and being required for their telomere association. Taken together, the findings point to a central role of CSL in telomere homeostasis with important implications for genomic instability of cancer stromal cells and beyond.
Medical subject headings
- Cancer-Associated Fibroblasts
- Carcinoma, Squamous Cell
- Fibroblasts
- Genomic Instability
- Immunoglobulin J Recombination Signal Sequence-Binding Protein
- Telomere