@article{bb98fabe741947e1bc1b452622d1123d,
title = "Human chromosome-specific aneuploidy is influenced by DNA-dependent centromeric features",
abstract = "Intrinsic genomic features of individual chromosomes can contribute to chromosome-specific aneuploidy. Centromeres are key elements for the maintenance of chromosome segregation fidelity via a specialized chromatin marked by CENP-A wrapped by repetitive DNA. These long stretches of repetitive DNA vary in length among human chromosomes. Using CENP-A genetic inactivation in human cells, we directly interrogate if differences in the centromere length reflect the heterogeneity of centromeric DNA-dependent features and whether this, in turn, affects the genesis of chromosome-specific aneuploidy. Using three distinct approaches, we show that mis-segregation rates vary among different chromosomes under conditions that compromise centromere function. Whole-genome sequencing and centromere mapping combined with cytogenetic analysis, small molecule inhibitors, and genetic manipulation revealed that inter-chromosomal heterogeneity of centromeric features, but not centromere length, influences chromosome segregation fidelity. We conclude that faithful chromosome segregation for most of human chromosomes is biased in favor of centromeres with high abundance of DNA-dependent centromeric components. These inter-chromosomal differences in centromere features can translate into non-random aneuploidy, a hallmark of cancer and genetic diseases.",
keywords = "aneuploidy, CENP, CENP-B boxes, centromere, chromosome segregation",
author = "Marie Dumont and Riccardo Gamba and Pierre Gestraud and Sjoerd Klaasen and Worrall, {Joseph T.} and {De Vries}, {Sippe G.} and Vincent Boudreau and Catalina Salinas-Luypaert and Maddox, {Paul S.} and Lens, {Susanne M.A.} and Kops, {Geert J.P.L.} and McClelland, {Sarah E.} and Miga, {Karen H.} and Daniele Fachinetti",
note = "Funding Information: The authors would like to thank: (from I. Curie, Paris) Cristina Bartocci, Oumou Goundiam, Sara Rivas Lopez, Amandine Grelier, and the Fachinetti, Basto and Drinnenberg team members for helpful suggestions and technical help. We would also like to thank L. Tovini (BCI, UK) for technical help; Christophe Escud{\'e} (Museum National d'Histoire Naturelle), Genevieve Almouzni (I. Curie), Peter Ly and Don Cleveland (UCSD, San Diego), Steve Henikoff (Fred Hutchinson Cancer Research Center), Arshad Desai (UCSD, San Diego), Mike Lampson (UPENN, US) for providing reagents; and Heidi Lane and Felix Bachmann (Basilea Pharmaceutica International, Switzerland) for providing the BAL27862 compound. We also thank the flow cytometry platform, the cell and tissue imaging facility (PICT-IBiSA, member of the French National Research Infrastructure France-BioImaging ANR10-INBS-04), and the sequencing platform at Institut Curie. High-throughput sequencing has been performed by the ICGex NGS platform of the Institut Curie supported by the grants ANR-10-EQPX-03 (Equipex) and ANR-10-INBS-09-08 (France G{\'e}nomique Consortium) from the Agence Nationale de la Recherche (“Investissements d'Avenir” program), by the Canceropole Ile-de-France and by the SiRIC-Curie program—SiRIC Grant « INCa-DGOS- 4654. D.F. receives salary support from the CNRS. D.F. has received support for this project from Labex « CelTisPhyBio », the Institut Curie, the ATIP-Avenir 2015 program, the program «Investissements d'Avenir» launched by the French Government and implemented by ANR with the references ANR-10-LABX-0038 and ANR-10-IDEX-0001-02 PSL. D.F. is also supported by the City of Paris, Emergence(s) 2018, an annual call for proposals that aim to help young researchers. R.G. was supported by AIRC post-doctoral fellowship for abroad research. P.S.M. is supported by National Science Foundation CAREER Award 1652512 and is William Burwell Harrison Fellow. S.M.A.L. is a member of Oncode Institute which is partly financed by the Dutch Cancer Society. Funding Information: The authors would like to thank: (from I. Curie, Paris) Cristina Bartocci, Oumou Goundiam, Sara Rivas Lopez, Amandine Grelier, and the Fachinetti, Basto and Drinnenberg team members for helpful suggestions and technical help. We would also like to thank L. Tovini (BCI, UK) for technical help; Christophe Escud{\'e} (Museum National d'Histoire Naturelle), Genevieve Almouzni (I. Curie), Peter Ly and Don Cleveland (UCSD, San Diego), Steve Henikoff (Fred Hutchinson Cancer Research Center), Arshad Desai (UCSD, San Diego), Mike Lampson (UPENN, US) for providing reagents; and Heidi Lane and Felix Bachmann (Basilea Pharmaceutica International, Switzerland) for providing the BAL27862 compound. We also thank the flow cytometry platform, the cell and tissue imaging facility (PICT‐IBiSA, member of the French National Research Infrastructure France‐BioImaging ANR10‐INBS‐04), and the sequencing platform at Institut Curie. High‐throughput sequencing has been performed by the ICGex NGS platform of the Institut Curie supported by the grants ANR‐10‐EQPX‐03 (Equipex) and ANR‐10‐INBS‐09‐08 (France G{\'e}nomique Consortium) from the Agence Nationale de la Recherche (“Investissements d'Avenir” program), by the Canceropole Ile‐de‐France and by the SiRIC‐Curie program—SiRIC Grant « INCa‐DGOS‐ 4654. D.F. receives salary support from the CNRS. D.F. has received support for this project from Labex « CelTisPhyBio », the Institut Curie, the ATIP‐Avenir 2015 program, the program «Investissements d'Avenir» launched by the French Government and implemented by ANR with the references ANR‐10‐LABX‐0038 and ANR‐10‐IDEX‐0001‐02 PSL. D.F. is also supported by the City of Paris, Emergence(s) 2018, an annual call for proposals that aim to help young researchers. R.G. was supported by AIRC post‐doctoral fellowship for abroad research. P.S.M. is supported by National Science Foundation CAREER Award 1652512 and is William Burwell Harrison Fellow. S.M.A.L. is a member of Oncode Institute which is partly financed by the Dutch Cancer Society. Publisher Copyright: {\textcopyright} 2019 The Authors",
year = "2020",
month = jan,
day = "15",
doi = "10.15252/embj.2019102924",
language = "English",
volume = "39",
journal = "EMBO Journal",
issn = "0261-4189",
publisher = "Springer Science and Business Media Deutschland GmbH",
number = "2",
}