Abstract
The chromosomal loci known as centromeres (CEN) mediate the equal distribution of the duplicated genome between both daughter cells. Specifically, centromeres recruit a protein complex named the kinetochore, that bi-orients the replicated chromosome pairs to the mitotic or meiotic spindle structure. The paired chromosomes are then separated, and the individual chromosomes segregate in opposite direction along the regressing spindle into each daughter cell. Erroneous kinetochore assembly or activity produces aneuploid cells that contain an abnormal number of chromosomes. Aneuploidy may incite cell death, developmental defects (including genetic syndromes), and cancer (>90% of all cancer cells are aneuploid). While kinetochores and their activities have been preserved through evolution, the CEN DNA sequences have not. Hence, to be recognized as sites for kinetochore assembly, CEN display conserved structural themes. In addition, CEN nucleosomes enclose a CEN-exclusive variant of histone H3, named CENP-A, and carry distinct epigenetic labels on CENP-A and the other CEN histone proteins. Through the cell cycle, CEN are transcribed into non-coding RNAs. After subsequent processing, they become key components of the CEN chromatin by marking the CEN locus and by stably anchoring the CEN-binding kinetochore proteins. CEN transcription is tightly regulated, of low intensity, and essential for differentiation and development. Under- or overexpression of CEN transcripts, as documented for myriad cancers, provoke chromosome missegregation and aneuploidy. CEN are genetically stable and fully competent only when they are insulated from the surrounding, pericentromeric chromatin, which must be silenced. We will review CEN transcription and its contribution to faithful kinetochore function. We will further discuss how pericentromeric chromatin is silenced by RNA processing and transcriptionally repressive chromatin marks. We will report on the transcriptional misregulation of (peri)centromeres during stress, natural aging, and disease and reflect on whether their transcripts can serve as future diagnostic tools and anti-cancer targets in the clinic.
Highlights
The chromosomal loci known as centromeres (CEN) mediate the equal distribution of the duplicated genome between both daughter cells
Not all alpha-satellite monomers contribute to human kinetochore activity, these are labeled as “inactive.” Human CEN contain alpha-satellite monomers of the A and B type, while lower primates only have A-type satellites (Alexandrov et al, 2001)
Since the same amount of CENP-A is renewed at each G1 stage, errors in CENP-A incorporation caused by abnormal CEN transcription, assembly factor activity, and/or post-translational modifications could permanently alter its levels at centromeric chromatin, contributing to chromosomal instability
Summary
Received: 06 September 2018 Accepted: 04 December 2018 Published: 21 December 2018. Transcription: Roles and Regulation . . . in Sickness and in Health. Aneuploidy may incite cell death, developmental defects (including genetic syndromes), and cancer (>90% of all cancer cells are aneuploid) While kinetochores and their activities have been preserved through evolution, the CEN DNA sequences have not. The replicated chromatids that are associated by cohesin rings bind to the microtubules of the metaphase spindle, which extend from two opposite spindle poles (Figure 1) This binding is mediated by kinetochores, each of which assembles on the centromere (CEN) of each chromatid. Not all alpha-satellite monomers contribute to human kinetochore activity, these are labeled as “inactive.” Human CEN contain alpha-satellite monomers of the A and B type, while lower primates only have A-type satellites (Alexandrov et al, 2001) Both monomers differ in a 17-bp sequence called A or B box (Figure 2C). For more detailed information about CEN we refer to Aldrup-MacDonald and Sullivan (2014); Bloom and Costanzo (2017); and Fukagawa and Earnshaw (2014)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
