Differential phase register of Hes1 oscillations with mitoses underlies cell-cycle heterogeneity in ER
AuthorsSabherwal, Nitin; orcid: 0000-0002-5808-6201
Rowntree, Andrew; orcid: 0000-0003-3220-0720
Marinopoulou, Elli; orcid: 0000-0002-6379-5168
Hourihane, Sean; orcid: 0000-0001-8327-2578
Kursawe, Jochen; orcid: 0000-0002-0314-9623
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AbstractHere, we study the dynamical expression of endogenously labeled Hes1, a transcriptional repressor implicated in controlling cell proliferation, to understand how cell-cycle length heterogeneity is generated in estrogen receptor (ER) breast cancer cells. We find that Hes1 shows oscillatory expression with ∼25 h periodicity and during each cell cycle has a variable peak in G1, a trough around G1-S transition, and a less variable second peak in G2/M. Compared to other subpopulations, the cell cycle in CD44 CD24 cancer stem cells is longest and most variable. Most cells divide around the peak of the Hes1 expression wave, but preceding mitoses in slow dividing CD44 CD24 cells appear phase-shifted, resulting in a late-onset Hes1 peak in G1. The position, duration, and shape of this peak, rather than the Hes1 expression levels, are good predictors of cell-cycle length. Diminishing Hes1 oscillations by enforcing sustained expression slows down the cell cycle, impairs proliferation, abolishes the dynamic expression of p21, and increases the percentage of CD44 CD24 cells. Reciprocally, blocking the cell cycle causes an elongation of Hes1 periodicity, suggesting a bidirectional interaction of the Hes1 oscillator and the cell cycle. We propose that Hes1 oscillations are functionally important for the efficient progression of the cell cycle and that the position of mitosis in relation to the Hes1 wave underlies cell-cycle length heterogeneity in cancer cell subpopulations. [Abstract copyright: Copyright © 2021 the Author(s). Published by PNAS.]
CitationProceedings of the National Academy of Sciences of the United States of America, volume 118, issue 45
DescriptionFrom PubMed via Jisc Publications Router
History: received 2021-07-29, accepted 2021-09-08
Publication status: ppublish
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No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in MLH1 and MSH2: A Prospective Lynch Syndrome Database StudyDominguez-Valentin, Mev; orcid: 0000-0001-7856-0057; email: Mev.Dominguez.Valentin@rr-research.no; Plazzer, John-Paul; orcid: 0000-0001-5114-4301; email: email@example.com; Sampson, Julian R.; email: Sampson@cardiff.ac.uk; Engel, Christoph; orcid: 0000-0002-7247-282X; email: firstname.lastname@example.org; Aretz, Stefan; orcid: 0000-0002-5228-1890; email: email@example.com; Jenkins, Mark A.; email: firstname.lastname@example.org; Sunde, Lone; email: email@example.com; Bernstein, Inge; email: firstname.lastname@example.org; Capella, Gabriel; orcid: 0000-0002-4669-7320; email: email@example.com; Balaguer, Francesc; orcid: 0000-0002-0206-0539; email: firstname.lastname@example.org; et al. (MDPI, 2021-06-28)Background. Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown. Objective. To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. Methods. Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity. Results. Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately. Conclusion. Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2.
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