mcb 134 final (lecs 19-23)

cell with mutation (genetic or environmental)

cis means inherited with the DNA, trans means not, ie transmitted through the cytoplasm.

hyperplasia = excessive growth by bypassing contact inhibition

dysplasia = abnormal cellular or tissue phentotype

tumor formation

metastasis to invade other tissues

evade growth suppressors, avoid immune destruction, accumulate defective genes, and mobilize

major contributor to cancer progression; contributes to resistance to treatments too

oncogenes are normally positive regulators of growth (often a kinase), tumor suppressors are negative regulators

excess cyclin leads to unrestrained cell cycle, leads to excessive growth and potentially tumors

chromosomal instability which changes in ploidy or telomere shortening. large chromosome rearrangements are strongly correlated with tumors

mutated/misexpressed oncogenes; anaeploidy and rearrangements that lead to altered protein stoichiometry

Spectral KaryotYpe

mix fluorescent tags so probes corresponding to a single chromosome are a unique color visualized by microscopes; can show aneuploidy, translocations, deletions, duplications, amplifications.

defects in segregation, replication, repair, checkpoints, etc result in disrupted cell cycle, altered gene expression and protein dosage, increased mutations, loss of heterozygosity

defective DNA repair or checkpoint pathways; active oncogenes, inactive tumor suppressors, altered stoichiometry to bypass barriers

defective spindle assembly checkpoint (SAC), drives cancer progression by altering gene dosage, stoichiometry of protein complexes

losing the chromosome or region containing wild-type gene, uncovers recessive mutations

mutations and rearrangements to bypass barriers leading to cancer

no, same pathway affected can lead to different types of cancers in different tissues

massive number of DSBs on one or a few chromosomes, then random rejoining

normal replication leaves 3’ ss overhang, due to requirement for primer templating lagging strand

loose ends could be degraded, activating DSB and checkpoint responses

loop where the end of a telomere is folded back

protein complex that protects telomere ends and helps form T-loops

both protect the ends through capping and looping, shelterin recruits telomerase

it is an enzyme carrying its own RNA molecule to add DNA repeats to the end of telomeres

loss of telomere end protection

unprotected telomere ends leads to high genomic instability

breakage fusion bridge cycles

telomere breaks off a chromosome, the chromosome replicates, so both do not have a telomere, then those ends fuse together. in anaphase, this forms a bridge where one centromere is pulling in one direction and the other is pulling in the opposite, resulting in breakage, not necessarily at the site they fused, resulting in uneven chromatids

senescence or apoptosis

telomerase adding repeats, or alternative lengthening of telomeres (ALT)

recombination between chromosomes/chromatids with short and long telomeres results in lengthening of shortened telomeres

prevents apoptosis; stabilizes aberrant genomes and allows cancer cell to proliferate

cells progress into mitosis without completing repair, resulting in genome instability, defective gene function, no apoptosis

cells progress through mitosis despite aberrant spindle-kinetochore interactions, resulting in aneuploidy/SCNAs

increasing probability of genome instability and allowing cells to cycle despite defects

Moderate levels of genome instability promotes cancer progression, but too much instability kills the cells

increase DNA damage or segregation defects to have too much genomic instability

continued instability, heterogeneity and selection leads to resistance to therapy and immune suppression

phenotypic or genetic differences, resulting from mutations or clonal evolution; it can complicate treatments and contribute to immune resistance

mutagenesis and selection

gene activation or repression and loss of modifiers can contribute to cancer progression and tumor heterogeneity

yes some cancers are driven by both

tumorigenic insulator loss leads to oncogene activation and tumor growth

epigenetic changes can serve as specific biomarkers used to diagnose specific cancers

yes; you can inactivate DNA & histone MTases, deacetylases, etc. to reverse silencing or activation

many side effects because of broad role epigenetic regulators play

single aa changes in canonical and variant histones that are prevalent in specific cancers. EX: H3.3K27M. Instead of being marked by H3K27me3, regions of the genome become "locked" in an active chromatin state, leading to dysregulated gene expression and promoting oncogenesis

it "poisons" epigenetic regulators. it ‘sequesters’ EZH2 from adding K27me3 elsewhere, and blocks additionemoval of other mods at K27

TOPBP1 likely acts as a scaffold protein, facilitating the assembly of protein complexes at the sites of DNA damage or chromosomal breaks. CIP2A directly interacts with
TOPBP1 and mediates its recruitment to DNA damage sites in mitosis, and has been proposed to play a role in tethering of broken chromosomal pieces. CIP2A is a protein that inhibits the activity of protein phosphatase 2A (PP2A). MDC1 likely functions to recruit other proteins, such as DNA repair factors and chromatin modifiers, to the sites of chromosomal breaks. This recruitment facilitates the formation of stable protein complexes that hold the broken chromosome fragments together during mitosis, thereby enabling their faithful inheritance. TOPBP1 interacts with MDC1 in mitosis through its BRCT1 and BRCT2 domains

drives acquisition of segmental deletions and inversions. significantly increased structural variant burden, as well as a significantly increased copy number burden

age, diet, stress

metabolic pathways impact availability of chemical precursors for DNA and histone modifications; Folate production required for SAM, affecting DNA mthylation

Folate is a critical cofactor in one-carbon metabolism, as it is required for the synthesis of SAM. Inadequate folate levels can lead to reduced SAM production, impairing DNA methylation reactions.

less folate = less methylation = overexpressed AVY = more yellow mouse; more folate = more methylation = underexpressed AVY = brown mouse (pseudo-agouti)

in arabidopsis, FLC = TF repressor of flowering; cold represses FLC and is maintained in warmth, explains vernalization. in drosophilia TF ATF2 mediates
H3K9me2/3 deposition when not phosphorylated; ATF2 is phosphorylated upon stress = fully red eyes

cold represses FLC and is maintained in warmth; the protein FRI forms nuclear condensates in response to cold, which helps repress the flowering gene FLC

diet; more methylation = worker, less methylation = queen

stress phosphorylates ATF2, which results in loss of H3K9me2/3 and leads to fully red eyes

longer life span, ethical and practical restraints, heterogeneity and environmental complexity

sometimes; can be inter-generational or trans-generational

intergenerational is direct exposure to zygote or germline, transgenerational they are not directly exposed

requires consistent environmental change, able to reverse effects when return to ‘normal’

F3 for humans, F2 for flies. Drosophila embryos develop externally. Therefore drosophila are never really "pregnant" and since only the egg itself is exposed and not the zygote's germ cells too (since the fertilized embryo develops externally)

model organisms; ATF2 in flies

TEI can involve utilizing small RNAs to target re-establishment of histone modifications or DNA methylation to specific parts of the genome

epigenetic reprogramming in germ line and zygotes

FRI accumulates and undergoes a specific structural change that leads to the formation of condensates that serve as hubs where various molecules, including FRI and other regulatory proteins, gather together to repress the activity of FLC

the cold-induced condensation of FRI is easily reversed by warmth, which suggests that the condensates serve as reservoirs allowing a rapid response to warm
temperature spikes. These rapid dynamics would buffer the shut-down of FLC transcription in the fluctuating temperatures of autumn, contributing to a requirement for the absence of warmth for FLC silencing

High temperature inhibits SET-25 mediated repression in the germ line, causing loss of H3K9me3. back at low temperatures, repression is gradually restored by
heterochromatin remodeling in each germline cycle

yes; primarily cis