Abstract
Faithful chromosome segregation is essential for the maintenance of genomic integrity and requires functional centromeres. Centromeres are epigenetically defined by the histone H3 variant, centromere protein A (CENP-A). Here we highlight current knowledge regarding CENP-A-containing chromatin structure, specification of centromere identity, regulation of CENP-A deposition and possible contribution to cancer formation and/or progression. CENP-A overexpression is common among many cancers and predicts poor prognosis. Overexpression of CENP-A increases rates of CENP-A deposition ectopically at sites of high histone turnover, occluding CCCTC-binding factor (CTCF) binding. Ectopic CENP-A deposition leads to mitotic defects, centromere dysfunction and chromosomal instability (CIN), a hallmark of cancer. CENP-A overexpression is often accompanied by overexpression of its chaperone Holliday Junction Recognition Protein (HJURP), leading to epigenetic addiction in which increased levels of HJURP and CENP-A become necessary to support rapidly dividing p53 deficient cancer cells. Alterations in CENP-A posttranslational modifications are also linked to chromosome segregation errors and CIN. Collectively, CENP-A is pivotal to genomic stability through centromere maintenance, perturbation of which can lead to tumorigenesis.
Highlights
Equal chromosome segregation during mitosis is critical for ensuring genome stability and for successful transmission of the genetic material to the daughter cells
The centromeric chromatin provides a platform for binding of the constitutive centromere-associated network (CCAN) by adopting a higher order structure that partitions centromere protein A (CENP-A)
While human centromeric DNA replicates mostly in late S phase [12,99], the deposition and assembly of CENP-A onto the chromatin occurs after exit from mitosis [98,100,101], when its loading chaperone Holliday Junction Recognition Protein (HJURP) [102,103] is active [104,105] (Figure 1A)
Summary
Equal chromosome segregation during mitosis is critical for ensuring genome stability and for successful transmission of the genetic material to the daughter cells. Despite the fact that human centromeres are found in this unique and complex genomic location, α-satellite DNA sequences are neither sufficient nor essential for centromere identity [8,17], as evidenced by the growing numbers of identified neocentromeres. CENP-A is a centromere specific variant of the canonical histone H3, initially identified in humans [21,22], that marks, maintains and propagates centromere function indefinitely in human cells and fission yeast [23]. Logsdon and colleagues have recently improved HAC technology bypassing the need for α-satellite centromeric repeats and CENP-B boxes and instead using the epigenetic machinery to initiate centromere identity [32,36]. CENP-A nucleosome seeding, leading to stable centromere and HAC formation and resulting in a new generation of HACs built without α-satellite DNA [32]
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