The centromere and kinetochore Flashcards
what is a centromere?
in three short parts
- A constricted region on a chromosome that joins sister chromatids
- The site where kinetochore is formed
- Specialised fragment of DNA, which allows sister chromatids to segregate
what is a kinetochore?
in three parts
- A multiprotein complex that forms at the centromere
- Specialised structure which allows sister chromatids to segregate during cell division
- Site on a chromosome where microtubules attach
how is centromeric chromatin different from euchromatin or heterochromatin?
nucelosomes of centromeric chromatin contain CENP-A (CenH) (centromeric marker)
CENP-A containing arrays are more condensed than canonical ones
(unqie set of histone markers, presence of centromeric proteins)
what is CENP-As main role?
defines the position of the centromere
whats the difference in association of CCAN and kinetochores with centromeres
cell cycle position
CCAN components are at centromeres throughout the cell cycle
Kinetochore components are at centromeres only during mitosis
what are the three major functions of the kinetochore?
- Capturing microtubules to form a connection between chromosomes and mitotic spindles
- Identifying incorrect attachments and repairing them
- Harnessing the force to generate movement of chromosomes during anaphase
when and where are kinetochores and CCAN complex organised
Kinetochores are assembled on centromeric chromatin in the beginning of mitosis
CCAN complex organised on CENPA containing nucelosomes and are present throughout the cell cycle
CCan is on cenpa nuclesomes, on top of which is the kmn network
what is the structural core of the kinetochore and what are its components?
the KMN network
three complexes: * KNL1/Spc105 complex * Mis12 complex * Ndc80 complex
the human KMN network is connected to the centromere via 2 separate pathways involving what proteins
centromere/kinetochore genes are misregulated in many cancers, what can overexpression of these genes indicate in the clinical status of cancer?
correlate with increased levels of genomic instability and several specific adverse tumour properties,
prognostically poor patient for survival for breast and lung cancers, especially early-stage tumours
levels of the overexpression can help to forecast patient response to adjuvant chemotherapy or radiotherapy
what are the two major proteins that help load CENP-A onto the DNA
MIS18 (marks where new CENPA is going to be loaded)
HJURP (directly participates in loading)
How is bi-polar attachment of chromosomes achieved?
the trial and error approach
Attachment of only one kinetochore is unstable – it is removed.
All attachments are unstable except for the bipolar. - Lasts for longer
Incorrect attachments are not stable and do not last.
Correct attachment becomes ‘locked’ in space
how are incorrect attachments repaired?
the chromosome passenger complex (CPC) aka Aurora B complex
when kinetochores are not properly attached, the tension is low the outer kinetochore is closer to the inner centromere where CPC is localised. Aurora B phosphorylates Ndc80 protein weakening interaction with the microtubules which are then released.
when the kinetochore is properly attached to microtubules, the high tension removes Ndc80 from the reach of Aurora B kinase and the attachments becomes stable
kinetochore has spring like properties that move away or towards the centromere under higher or lower tension
how are incorrect attachments repaired?
the chromosome passenger complex (CPC) aka Aurora B complex
when kinetochores are not properly attached, the tension is low the outer kinetochore is closer to the inner centromere where CPC is localised. Aurora B phosphorylates Ndc80 protein weakening interaction with the microtubules which are then released.
when the kinetochore is properly attached to microtubules, the high tension removes Ndc80 from the reach of Aurora B kinase and the attachments becomes stable
kinetochore has spring like properties that move away or towards the centromere under higher or lower tension
what are the functions for each of the Aurora kinases A B and C?
- Aurora A kinase is localised primarily to centrosomes and it controls centrosomal activities, e.g. mitotic spindle formation
- Aurora B kinase is a component of CPC and its localisation changes from inner-centromeric to microtubules of the central spindle and midzone. It participates in chromosome condensation, segregation and cytokinesis
- Aurora C is involved in meiosis
what happens witch Aurora B depletion in cells?
Not so well aligned at the metaphase plate and chromosome progression is already limited
inhibitors targetting aurora kinases are examples of what types of drugs used in cancer therapy
anti-mitotic drugs
what happens when we counteract aurora kinase overexpression in cancer cells?
some cancer cells get addicted to the overexpession so when we decrease it the cell suffer
aurora kinase inhibition leads to cell death by apoptosis
- aurora A inhibition -> monopolar spindle, prolonged mitosis or perturbed prometaphase then sever aneuploidy and so cell deaath
- aurora B inhibition -> unaligned chromosomes then premature mitotic exit and polyploidy and so cell death
how do anti-mitotic drugs work in cancer therapy?
Because cancer cells proliferate uncontrollable, anti-mitotic drugs should stop cells from dividing, as a consequence, stop the tumour from further growth. Anti-mitotic drugs are expected to arrest cell cycle for extended period of time
give three examples of targets for anti-mitotic drugs
- microtubules, as major components of mitotic spindle (stabilisers, de-stabilisers)
- kinesins, as major regulators of microtubule dynamicity
- mitotic kinases, as major regulators of cell cycle and cell division (CDKs, PLKs, Aurora kinases, Wee 1 kinases)
what proteins make up the cohesin complex?
SMC subunits = SMC1 and SMC3
non-SMC subunits = SCC3 and RAD21
when is the cohesin complex loaded and unloaded from the chromosomes?
It is loaded on chromosomes during G1 phase, after DNA replication it holds sister chromatids together.
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Its release from chromosome arms in prophase coincides with the axial compression of chromosomes during mitosis
Along with CTCF it defines borders of chromatin units during interphase
when is the cohesin complex loaded and unloaded from the chromosomes?
It is loaded on chromosomes during G1 phase, after DNA replication it holds sister chromatids together.
.
Its release from chromosome arms in prophase coincides with the axial compression of chromosomes during mitosis
Along with CTCF it defines borders of chromatin units during interphase
what are the functions of cohesin in mitosis?
- Sister chromatid cohesion (at centromeres)
- Holding together sister centrioles
