Human chromosome-specific aneuploidy is influenced by DNA-dependent centromeric features

TY - JOUR

T1 - Human chromosome-specific aneuploidy is influenced by DNA-dependent centromeric features

AU - Dumont, Marie

AU - Gamba, Riccardo

AU - Gestraud, Pierre

AU - Klaasen, Sjoerd

AU - Worrall, Joseph T

AU - De Vries, Sippe G

AU - Boudreau, Vincent

AU - Salinas-Luypaert, Catalina

AU - Maddox, Paul S

AU - Lens, Susanne Ma

AU - Kops, Geert Jpl

AU - McClelland, Sarah E

AU - Miga, Karen H

AU - Fachinetti, Daniele

N1 - © 2019 The Authors.

PY - 2019/11/21

Y1 - 2019/11/21

N2 - 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.

AB - 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.

U2 - 10.15252/embj.2019102924

DO - 10.15252/embj.2019102924

M3 - Article

C2 - 31750958

SN - 0261-4189

SP - e102924

JO - EMBO Journal

JF - EMBO Journal

ER -