18.01.02 Chromosome structure in humans Flashcards
What is a chromosome?
Chromatin fibre folded and coiled into a compact arrangement found within the cell nucleus. Only visible during cell division when DNA becomes more tightly packed.
What is the structure of a chromosome?
Constricted by the centromere. Centromere placement divides chromosomes into three major categories; metacentric, submetacentric, acrocentric
Define what a centromere is. What is the function of a centromere?
Centromere: region of highly specialised chromatin providing the foundation for kinetochore assembly and site for sister chromatid attachment.
Essential for accurate chromosome segregation during cell division. Centromere divides at mitosis and meiosis II so chromatids can migrate to opposite poles
Errors in centromere/kinetochore function lead to chromosome instability and aberrant division.
What is the structure of a centromere?
Composed of various families of repetitive satellite DNA i.e. a-satellite DNA (171bp repeat seq) and b-satellite DNA
3 centromeric subdomains, CDE-1, 11 and -111. Mutations in CDE-111 completely disrupt centromere function
There are ~20 known proteins associated with human centromeres (CENPs), classed into two groups. Describe these two groups.
Divided based on their spatial positioning throughout the cell cycle.
1) Those constitutively associated with the centromere which are thought to have a role in kinetochore formation e.g. CENP-A, -B and _C
2) Passenger proteins associate with the centromere transiently through the cell cycle and have a diverse range of roles in cell division e.g. spindle capture, transition to anaphase, sister chromatid adhesion.
Describe premature centromere division (PCD).
Age-dependent occuring in women
Rod-shaped C chromosome without discernible centromeres
May be possible cause of age-related X-chr aneuploidy
Describe premature chromatid separation. Give an example of a disease this is present in and the underlying molecular pathology of this disease.
Separate and splayed chromatids with discernible centromeres. Seen in almost all metaphase chromosomes.
Roberts syndrome (AR, ESCO2, 8p21.1) caused by centromere malfunction ESCO2 encodes an acetyltransferase required to hold the sister chromatids in place in S phase. Mutations lead to delayed cell division and increased cell death.
Describe the kinetochore.
Large multiprotein complex (>80)
Assembles on centromere and acts as a point of attachment for microtubules/spindle fibres.
Essential for segregation during mitosis
Formed at each centromere during late prophase
Kinetochore positioned on the side of each chromatid facing the spindle pole which it will move towards during anaphase
What is a neocentromere? What are the two forms?
Rare cases neocentromeres form at novel locations e.g. on acentric fragment which prevents it being lost during cell division.
1) Class 1 marker chromosomes are the most common - inverted duplication of distal part of chromosome
2) Class 2 marker chromosomes - from interstitial duplication.
Have a similar chromatin organisation to normal centromeres; form a primary constriction, assembly a functional kinetochore, but lack a-satellite DNA and CENP-B. C-band negative.
Describe the function of a telomere.
1) Maintain structural integrity
2) Prevents shortening of chromosomes at each round of cell division
3) Important for chromosome positioning and help to establish the 3D architecture of the nucleus.
4) Consists of 3-20kb of tandem TTAGGG repeats associated with a variety of telomere-binding proteins
Describe the structure of a telomere.
Highly conserved gene poor, DNA-protein complexes that cap the ends of chromosomes and are required to maintain normal structure and function of a cell.
What is the function of telomerase?
Telomere length is highly variable and telomere activity absent in adult cells except those with high proliferation.
Cells that lack telomerase shorten progressively and is a way of counting cell divisions and is related to senescence and ageing. Cancer activates telomerase leading to uncontrolled replication.
Carries an 11nt seuqence with is antisense to the TTAGGG telomere sequence and this acts as a template to prime extended DNA synthesis of telomeric sequence of the leading strand, providing a template for DNA polymerase to complete synthesis of the lagging strand.
Give examples of two diseases associated with telomere malfunction.
1) Dyskeratosis congenital (DC):
2) Cri-du-chat syndrome
3) Anaplastic anaemia
What is the nuclear organising region (NOR)?
Responsible for organising nucleolus structure and contain ~200rRNA genes required for protein synthesis.
Located on p12 regions on acrocentrics (satellite stalks)
Contains rRNA that is required into a transcriptional unit and repeated 50-60 times.
When active it stains darkly with silver nitrate.
Describe the replication origin (ORs)
Cis-acting DNA sequences which bind proteins ready for DNA replication
Multiple sites across the chromosome
AT-rich
Recognised by a 6-protein complex
