DNA Sequence-Specific Binding of CENP-B Enhances the Fidelity of Human Centromere Function

Daniele Fachinetti; Joo Seok Han; Moira A. McMahon; Peter Ly; Amira Abdullah; Alex J. Wong; Don W. Cleveland

doi:10.1016/j.devcel.2015.03.020

DNA Sequence-Specific Binding of CENP-B Enhances the Fidelity of Human Centromere Function

Daniele Fachinetti, Joo Seok Han, Moira A. McMahon, Peter Ly, Amira Abdullah, Alex J. Wong, Don W. Cleveland

Research output: Contribution to journal › Article › peer-review

161 Scopus citations

Abstract

Human centromeres are specified by a stably inherited epigenetic mark that maintains centromere position and function through a two-step mechanism relying on self-templating centromeric chromatin assembled with the histone H3 variant CENP-A, followed by CENP-A-dependent nucleation of kinetochore assembly. Nevertheless, natural human centromeres are positioned within specific megabase chromosomal regions containing α-satellite DNA repeats, which contain binding sites for the DNA sequence-specific binding protein CENP-B. We now demonstrate that CENP-B directly binds both CENP-A's amino-terminal tail and CENP-C, a key nucleator of kinetochore assembly. DNA sequence-dependent binding of CENP-B within α-satellite repeats is required to stabilize optimal centromeric levels of CENP-C. Chromosomes bearing centromeres without bound CENP-B, including the human Y chromosome, are shown to mis-segregate in cells at rates several-fold higher than chromosomes withCENP-B-containing centromeres. These data demonstrate a DNA sequence-specific enhancement by CENP-B of the fidelity of epigenetically defined human centromere function.

Original language	English (US)
Pages (from-to)	314-327
Number of pages	14
Journal	Developmental cell
Volume	33
Issue number	3
DOIs	https://doi.org/10.1016/j.devcel.2015.03.020
State	Published - May 4 2015
Externally published	Yes

ASJC Scopus subject areas

Molecular Biology
Biochemistry, Genetics and Molecular Biology(all)
Developmental Biology
Cell Biology

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10.1016/j.devcel.2015.03.020

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@article{82d294678c3f4945a868d19b2f9aad8a,

title = "DNA Sequence-Specific Binding of CENP-B Enhances the Fidelity of Human Centromere Function",

abstract = "Human centromeres are specified by a stably inherited epigenetic mark that maintains centromere position and function through a two-step mechanism relying on self-templating centromeric chromatin assembled with the histone H3 variant CENP-A, followed by CENP-A-dependent nucleation of kinetochore assembly. Nevertheless, natural human centromeres are positioned within specific megabase chromosomal regions containing α-satellite DNA repeats, which contain binding sites for the DNA sequence-specific binding protein CENP-B. We now demonstrate that CENP-B directly binds both CENP-A's amino-terminal tail and CENP-C, a key nucleator of kinetochore assembly. DNA sequence-dependent binding of CENP-B within α-satellite repeats is required to stabilize optimal centromeric levels of CENP-C. Chromosomes bearing centromeres without bound CENP-B, including the human Y chromosome, are shown to mis-segregate in cells at rates several-fold higher than chromosomes withCENP-B-containing centromeres. These data demonstrate a DNA sequence-specific enhancement by CENP-B of the fidelity of epigenetically defined human centromere function.",

author = "Daniele Fachinetti and Han, {Joo Seok} and McMahon, {Moira A.} and Peter Ly and Amira Abdullah and Wong, {Alex J.} and Cleveland, {Don W.}",

note = "Funding Information: The authors thank William C. Earnshaw (Wellcome Trust Centre for Cell Biology, University of Edinburgh), P. Kalitsis (Murdoch Childrens Research Institute Victoria, Australia), A. Desai, R. Khaliullin, Neil Hattersley, and C. Bartocci (Ludwig, La Jolla, California), F. Dibazar, Y. Arbely, B. Vitre, and others members of the Cleveland lab for helpful suggestions. We thank P. Maddox (University of North Carolina), I. Cheeseman (MIT, Boston), A. Desai (Ludwig, La Jolla, California), P. Kalitsis (Murdoch Children{\textquoteright}s Research Institute Victoria, Australia), H. Masumoto (Kazusa DNA Research Institute, Japan), and B.E. Black (University of Pennsylvania, Philadelphia) for providing reagents. We also thank the Neuroscience Microscopy Shared Facility (P30 NS047101, University of California, San Diego) and the FACS facility in the Sanford Consortium for Regenerative Medicine, La Jolla, California. This work was supported by a grant from the NIH (R01-GM 074150 to D.W.C.). D.W.C. receives salary support from the Ludwig Institute for Cancer Research. Publisher Copyright: {\textcopyright} 2015 Elsevier Inc.",

year = "2015",

month = may,

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doi = "10.1016/j.devcel.2015.03.020",

language = "English (US)",

volume = "33",

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T1 - DNA Sequence-Specific Binding of CENP-B Enhances the Fidelity of Human Centromere Function

AU - Fachinetti, Daniele

AU - Han, Joo Seok

AU - McMahon, Moira A.

AU - Ly, Peter

AU - Abdullah, Amira

AU - Wong, Alex J.

AU - Cleveland, Don W.

N1 - Funding Information: The authors thank William C. Earnshaw (Wellcome Trust Centre for Cell Biology, University of Edinburgh), P. Kalitsis (Murdoch Childrens Research Institute Victoria, Australia), A. Desai, R. Khaliullin, Neil Hattersley, and C. Bartocci (Ludwig, La Jolla, California), F. Dibazar, Y. Arbely, B. Vitre, and others members of the Cleveland lab for helpful suggestions. We thank P. Maddox (University of North Carolina), I. Cheeseman (MIT, Boston), A. Desai (Ludwig, La Jolla, California), P. Kalitsis (Murdoch Children’s Research Institute Victoria, Australia), H. Masumoto (Kazusa DNA Research Institute, Japan), and B.E. Black (University of Pennsylvania, Philadelphia) for providing reagents. We also thank the Neuroscience Microscopy Shared Facility (P30 NS047101, University of California, San Diego) and the FACS facility in the Sanford Consortium for Regenerative Medicine, La Jolla, California. This work was supported by a grant from the NIH (R01-GM 074150 to D.W.C.). D.W.C. receives salary support from the Ludwig Institute for Cancer Research. Publisher Copyright: © 2015 Elsevier Inc.

PY - 2015/5/4

Y1 - 2015/5/4

N2 - Human centromeres are specified by a stably inherited epigenetic mark that maintains centromere position and function through a two-step mechanism relying on self-templating centromeric chromatin assembled with the histone H3 variant CENP-A, followed by CENP-A-dependent nucleation of kinetochore assembly. Nevertheless, natural human centromeres are positioned within specific megabase chromosomal regions containing α-satellite DNA repeats, which contain binding sites for the DNA sequence-specific binding protein CENP-B. We now demonstrate that CENP-B directly binds both CENP-A's amino-terminal tail and CENP-C, a key nucleator of kinetochore assembly. DNA sequence-dependent binding of CENP-B within α-satellite repeats is required to stabilize optimal centromeric levels of CENP-C. Chromosomes bearing centromeres without bound CENP-B, including the human Y chromosome, are shown to mis-segregate in cells at rates several-fold higher than chromosomes withCENP-B-containing centromeres. These data demonstrate a DNA sequence-specific enhancement by CENP-B of the fidelity of epigenetically defined human centromere function.

AB - Human centromeres are specified by a stably inherited epigenetic mark that maintains centromere position and function through a two-step mechanism relying on self-templating centromeric chromatin assembled with the histone H3 variant CENP-A, followed by CENP-A-dependent nucleation of kinetochore assembly. Nevertheless, natural human centromeres are positioned within specific megabase chromosomal regions containing α-satellite DNA repeats, which contain binding sites for the DNA sequence-specific binding protein CENP-B. We now demonstrate that CENP-B directly binds both CENP-A's amino-terminal tail and CENP-C, a key nucleator of kinetochore assembly. DNA sequence-dependent binding of CENP-B within α-satellite repeats is required to stabilize optimal centromeric levels of CENP-C. Chromosomes bearing centromeres without bound CENP-B, including the human Y chromosome, are shown to mis-segregate in cells at rates several-fold higher than chromosomes withCENP-B-containing centromeres. These data demonstrate a DNA sequence-specific enhancement by CENP-B of the fidelity of epigenetically defined human centromere function.

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JO - Developmental cell

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ER -

DNA Sequence-Specific Binding of CENP-B Enhances the Fidelity of Human Centromere Function

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