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Nov 28th , 2013 - Genomic Stability and Introduction to Angiogenesis

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York University
BIOL 4010
Keith Wheaton

Nov 28th , 2013 - one of the key enzymes involved in genomic stability and recruitments of repair proteins is PARP ( poly ADP-ribose polymerase 1) -if DNA damage area PARP is recruited and makes huge chains of polymerized ADP ribose tail allowing binding of other repair enzymes to fix the DNA -used in chemotherapy via inhibition of this PARP enzyme In most cells when PARP is inhibited then its compensated by homologous recombination : important for BRCA1 and BRCA2 derived cancers where recombination is inhibited naturally in the cancer Synthetic lethality: many gene defects leading to cell death -if we cause enough damage in cancer cells then the cell can die if specific pathways are knocked out example : BRCA2 mutants are extremely sensitive to PARP inhibitors ( known as KU0058948) Chromosomal Translocations caused by: - un-repaired dsDNA breaks ex: BCRA mutations -misfiring of mechanisms for rearranging immunoglobulin ex: BCR-ABL & MYC - breakage-fusion cycles at crisis when telomeres are critically short ex: P53 mutation ** There is a disequilibrium in every chromosome in cancer cells -they are called hot spots , in figure the lines connecting the chromosomes signify the translocations in btw chromosomes - almost all advanced cancers have a high number of lines : translocations ! - the wheel look a like diagrams are allied Circos Plots - green lines in the plot are normal rearrangements but shown because they probably have amplified or any mutation leading to deletions , insertions etc Localized firestorms - not very known - areas that almost always show massive translocations in all cancer types - there are deletions , tail to tail inverted , tandem dup-type and head to tail inverted : in any given chromosome explained by non-homologous enjoining in getting the pieces back together but why the pieces shatter away we don't know yet *There is always some variations on number of chromosomes in cancer cells - in normal cells there may be variations too but for the most part is fairly rare -when cancer cells are looked at ex: breast cancer showing chromosomes number get amplified : causing disequilibrium between chromosomal numbers thus no proper mitosis chromosome segregation Chromosomal vs Microsatellite Instability - essentially both mutually exclusive - microsatellite instability doesn't necessarily show chromosomal instability and vice versa - they are basically two different mutated phenotypes that can both lead to cancer -there are exceptions where both can be present but rare Spindle Assembly Checkpoint - chromosomal instability relates to mitosis and the specific checkpoints within the cell cycle - spindle apparatus observes proper alignment of chromosomes and then it allows cells to continue the cell cycle - there is a spindle checkpoint so that the two homologues of any chromosome are equally distributed between the two cells to be formed - important pace centre of mitosis in general is APC ( anaphase promoting complex) which when its working the activity of cell cycle occurs - when APC is halted then the cell can't continue the cycle - the microtubule usually connects to kinetochore , there is a protein known as CENP-E motor protein that sees is microtubule is attached or not by recruiting many other kinases ex: Mad1 and Mad2 bind to kinetochore when no microtubule is present - Mad2 ( leaves Mad1-2 complex via phosphorylation by another kinase) inhibits cdc20 therefore APC gets shut down thus no mitosis - therefore cancer cells can affect both Mad 1 and Mad2 which would lead to APC not working properly ANGIOGENESIS - LECTURE 9 - recruiting vasculature( blood vessels) to allow cancer cell survival "feeding" -all tumors consists of different cell types, but not entire tumour is malignant - in tumor types there is epithelia and stroma ( supporting cells= non-neoplastic cells) ; almost every tumours have these two cell types - supporting tissue : fibroblasts , vasculature of cell , can be present or not depending on tumour type and how aggressive and independent it is A heterotypic Cell Biology - many years cancer cells were viewed as working alone ( reductionist view) - grow , thrive on their own - the new view shows many different cell types to be part of the process , active roles within tumour which if taken away tumour would not survive either - changes in cancer cells such as mutations allow to take control and advantage of normal pathways in stroma cells surrounding it The tumour microenvironment - cancer stem cells , cancer associated fibroblasts , endothelial cells , pericytes, inflammatory
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