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#centromere

14 public questions tagged with this topic.

Cell Division

What is the primary function of the centromere during mitosis?

Centromere is specialized chromosomal domain that appears as primary constriction in metaphase chromosomes and functions as essential platform for kinetochore assembly linking chromosomes to spindle microtubules and providing tension sensor. Human centromeres built on megabases of alpha-satellite repeat DNA enriched with nucleosomes containing histone variant CENP-A replacing H3, deposited by chaperone HJURP in G1, epigenetically marking locus independent of sequence alone. CENP-A recruits constitutive centromere-associated network including CENP-C, CENP-I, CENP-H, CENP-T-W-S-X complex forming inner kinetochore bridging DNA to outer kinetochore KMN network composed of KNL1 scaffold, Mis12 complex, and Ndc80 complex that directly binds microtubule plus ends via calponin homology domains. This trilaminar structure translates microtubule dynamics into chromosome movement and recruits spindle assembly checkpoint proteins Mad1, Mad2, Bub1 until biorientation satisfied. Artificial chromosome assays show alpha-satellite plus CENP-B boxes required for stable inheritance, proving centromere function indispensable for segregation during mitosis and meiosis. This circuitry is highly conserved across eukaryotes, integrating growth factor signals, DNA damage surveillance, and developmental cues, and its disruption frequently underlies oncogenesis, providing targets for checkpoint inhibitors and cancer therapeutics.

Ref: Fukagawa & Earnshaw, Dev Cell 2014, Centromere Function. Alberts 7th ed., Chapter 17, Centromere.

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Cytoskeleton Cilia Flagella Centrosome Nucleus and Chromosomes

Two chromosomes are examined. Chromosome X has two equal arms, while chromosome Y has its centromere at the terminal end

A metacentric chromosome has a centrally positioned centromere and two equal arms. A telocentric chromosome has a terminal centromere. Classification therefore requires relating arm lengths to centromere position.

Ref: NCERT Class 11 Biology Chapter 8: Cell: The Unit of Life Cytoskeleton Cilia Flagella Centrosome Nucleus and Chromosomes

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Chromosome variations

Pericentric inversion includes

Pericentric inversion includes centromere within inverted interval, so breakpoints lie on opposite arms: one in short arm p and one in long arm q. Reorientation moves centromere position, altering arm ratio and possibly changing metacentric to submetacentric morphology. This change can be detected cytogenetically as altered p/q length. In heterozygotes, pairing forms inversion loop to align homologous sequences, and single crossover inside loop yields chromatids with duplication and deletion of terminal segments, leading to unbalanced gametes and risk for recombinant offspring with clinical abnormalities.

Ref: Hartl & Jones, Genetics, 8th ed., Chapter 12: Inversion Mechanics; Griffiths Chapter 8

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Chromosome variations

Inversion that does not include centromere is called

An inversion arises when a chromosome breaks at two points and the intervening segment reinserts reversed, changing gene order 180 degrees. Classification depends on centromere position relative to breakpoints. If both breaks occur in same arm and the inverted segment excludes centromere, it is paracentric, meaning alongside centromere. Because centromere remains outside, crossover inside inversion loop produces dicentric bridge and acentric fragment causing inviability. Pericentric inversions include centromere and alter arm ratio. Breakpoint mapping and cytogenetic banding patterns distinguish types for clinical diagnosis and risk counseling.

Ref: Nussbaum et al., Thompson & Thompson, Chapter 5: Paracentric vs Pericentric Inversions

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Nucleosome Packing

CENP-A mainly localizes to:

CENP-A containing nucleosomes localize almost exclusively to functional centromere, not dispersed throughout chromosome arms. High resolution immunofluorescence and chromatin immunoprecipitation sequencing show discrete foci at primary constriction colocalizing with inner kinetochore markers CENP-C and CENP-T during interphase and mitosis. At centromere CENP-A directly recruits CCAN network initiating kinetochore assembly ensuring spindle microtubule attachment and checkpoint signaling. It does not accumulate at telomeres containing TTAGGG repeats protected by shelterin, nor at nucleolar organizer regions containing rDNA, nor at replication origins firing genome wide.

Ref: Earnshaw and Migeon CENP-A Localization; Lodish et al., Chapter 19: CENP-A Mainly Localizes to Centromere

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Nucleosome Packing

CENP-A is a variant of histone:

Centromeric chromatin contains distinctive histone variant CENP-A that epigenetically specifies centromere location independent of underlying DNA sequence in most eukaryotes. CENP-A resembles canonical histone H3 in histone fold domain sharing about sixty percent similarity, but possesses divergent N-terminus and loop1 centromere targeting domain CATD directing specific deposition via HJURP chaperone during G1. It replaces H3 in subset of nucleosomes at active centromere creating specialized octamer recruiting inner kinetochore. H1 is linker histone, H2A variants include H2A.Z, H4 lacks centromeric-specific variant analogous to CENP-A functionally.

Ref: Palmer et al., 1987 PNAS; Alberts et al., Molecular Biology of the Cell, Chapter 4: CENP-A is Variant of H3

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