Cell Cycle & errors in mitosis/meiosis Flashcards
How is the cell cycle regulated?
Checkpoints. Regulated by heterodimeric protein kinases composed of cyclins (regulatory subunit) and cyclin-dependent kinases (CDKs - inactive in absence of cyclin). Phosphorylate target proteins to orchestrate co-ordinated entry into next phase of the cell cycle.
What proteins are involved in the G1/S Checkpoint
cyclin D forms phosphorylates retinoblastoma protein, relieves inhibition of E2F transcription factor. Cyclin E now expressed binds to CDK2. G1-S transition.
What proteins are involved in the G2/M Checkpoint
CDK1 activated by cyclin activating kinase and wee1 protein enabling CDK1-cyclin B formation. G2-M transition.
Metaphase/spindle checkpoint
Anaphase promoting complex activated relieves inhibition of ‘separase’ = spindle cut and sister chromatids separate. Anaphase entry.
What are the stages of the cell cycle?
G0 - resting G1 - growth (proteins/RNA synthesised) S - synthesis G2 - growth M - mitosis
What are the stages of mitosis?
Prophase - spindle fibres appear. Chromosomes condense.
Prometaphase - spindle fibres attach
Metaphase - chromosomes (bivalents) align
Anaphase - centromeres divide. Sister chromatids opposite poles.
Telophase - nuclear membrane reforms and chromosomes decondense.
Cytokinesis - cytoplasm divides.
What is the role of p53?
Important through G1/S and G2/M checkpoints. Dna damage - p53 activated - inhibits progression.
What is the main difference between meiosis and mitosis?
Chromosome number halves, recombination.
What are the stages of meiosis?
Prophase I - crossing over
(Leptotene - chromatin condenses
Zygotene - mat and pat homologues pair to form bivalents)
Pachytine - all homologues have paired (synapsis)
Pachtene late) chromosomes cross over and recombine. Two non-sister chromatids cross over the other 2 remain unaltered.
Diplotene - homologues start to separate but are held together by chiasmata.
Diakinesis - nuclear envelope breaks down)
Metaphase I - spindle formed, bivalents align
Anaphase I - homologous chromosomes drawn apart. Chromatids remain together
Telophase I - chromosomes at poles haploid daughter cells form.
Prophase/Metaphase II - nuclear envelope breaks down. New spindle forme,d cromosomes align.
Anaphase II - separation of centromeres, migration of sister chromatids to opposite poles.
Telophase II - further cell division forming 2 haploid cells (4 in total).
What are the main processes resulting in chromosomal abnormality (numerical)?
Non disjunction or anaphase lag. Leads to mosaicism if occurred during mitosis, or disomic and nullisomic gametes if occurred during M1 or M2.
Describe the mitotic spindle
Formed from tubulin-based microtubules and microtubule-associated proteins. Polar fibres, which extend from the two poles of the spindle towards the equator, develop at prophase. Kinetochore fibers do not develop until prometaphase. These fibres attach to the kinetochore, a large multiprotein structure attached to the centromere of each chromatid and extend in the direction of the spindle poles.
What is nondisjunction?
Nondisjunction is the failure of homologous chromosomes to segregate symmetrically at cell division. It is remarkably frequent, therefore ~1/3rd of human conceptions are trisomic or monosomic.
What is the outcome of nondisjunction in Meiosis?
Meiosis I - 2:0 (one daughter cell with 2 chromosomes the other with none). Usually 3 different alleles (parental heterozygous).
Meiosis II - chromatids fail to separate - two normal gametes, one disomic gamete and one nullisomic gamete (produces 2 identical variant chromosomes as from the same parent). At fertilisation, trisomic or monosomic fetus. MEIOSIS I for T13, 18 21. Most cases of mosaic trisomy/disomy 13, 18, 21, and X arise due to nondisjunction in a postzygotic mitosis in a conceptus that is initially trisomic for an autosome
What are the possible causes of non disjunction?
Abnormality in the proteins which move and separate chromosomes during meiosis. For example motor proteins chromosomes misaligned. Increased maternal age - degenerating spindle apparatus.
What is anaphase lag?
Anaphase lag describes the delayed movement during anaphase of one homologous chromosome in mitosis, or one chromatid in meiosis. The chromosome fails to connect to the spindle apparatus, or is drawn to the pole late, and fails to be included in the nucleus of one of the daughter cells. This results in one normal and one monosomy cell, the lagging chromosome is lost.
Describe recombination
Process
Alignment of two homologous DNA strands.
Breakage of each strand (DSB - sstails with 3’ termini).
Equal exchange of DNA segments between the 2 strands (inter-homolog sinlge-end invasion by the ss tails).
DHJs resolved in to cross-over products.
Sealing of the resultant recombined DNA molecules by ligase = two gametes with parental genotype and two with recombinant genotype.
What processes introduce genetic diversity
Independent assortment and recombination.
