Lecture 11 Flashcards
What are the principle lesions that lead to chromosomal aberrations?
Double strand breaks
Where are sister chromatids held together?
Centromere
What effector do DSBs activate that then guide the cell towards either senescence or apoptosis?
p53
What is nondisjunction?
When members of a chromosome pair fail to separate during anaphase of meiosis
What does nondisjunction result in?
Gametes with an incorrect number of chromosomes
What is chromothripsis?
Shattering of the chromosome into thousands of pieces
What causes chromothripsis?
Massive double strand breaks, followed by rearrangements, reassembly, and fusion
Chromothripsis is commonly associated with what two disorders?
Fanconi anaemia and colorectal cancer
What is a pericentric inversion?
A single chromosome with two breaks swaps the location of its two fragments
What is a paracentric aberration?
Both points of exchange lie on same side of centromere
What are interchanges?
Exchange of two sister chromatids between separate chromosomes
What is the Philadelphia Chromosome?
Mutated chromosome due to translocation between chromosomes 9 and 22
What condition does the Philadelphia Chromosome cause?
Chronic myelogenous leukemia (CML)
What chromosome aberration causes Burkitt Lymphoma?
Translocation between chromosomes 8 and 14
What does the translocation between chromosomes 8 and 14 cause?
Translocation of MYC oncogene from chromosome 8 to the heavily expressed heavy chain IG gene region of chromosome 14
What are epigenetics?
Heritable non-genetic modifications
What are CpG islands?
Repeats of C and G where methylation control occurs
Relative to the gene, where are CpG islands typically found?
Close to the start of the promoter
What does methylation of the promoter do?
Prevents binding of transcription factors, thus inhibiting gene expression
Is epigenetic methylation inheritable?
Yes
In cancers, what genes are methylated?
Tumor suppressor genes
In cancers, what genes are unmethylated?
Oncogenes
What is a nucleosome?
DNA wrapped around a core of 8 histone proteins
What protein locks the DNA around the histone complex?
Linker histone H1
What is the epigenetic site of histone proteins?
N-terminal tails
What are four types of histone modification?
Acetylation, methylation, phosphorylation, and ubiquitination
What is heterochromatin?
Compact DNA clustered near nucleolus and nuclear membrane
What is euchromatin?
Dispersed DNA that occupies most of the nuclear region
In what kind of chromatin is transcription “on?”
Euchromatin
What histone modification promotes transcription?
Acetylation
What histone modification inhibits transcription?
Methylation
What class of enzymes methylates DNA?
DNA methyltransferases
How many DNA methyltransferases do humans have?
3
Which is the “maintenance” methyltransferase responsible for copying methylation patterns during replication?
DNMT1 (methyltransferase 1)
Ubiquitination is a form of ____
Post-translational modification
Ubiquitin is found covalently bound to what amino acid residue?
Lysine
What does ubiquitin regulate?
Protein degradation, cellular location, endocytic trafficking, histones
What is the function of histone ubiquitin ligases (HULs)?
Add ubiquitin to histone complexes
What notable oncogene is a part of the HUL?
BRCA1
Loss of BRCA1 leads to a loss of what?
Histone ubiquitination
What 2 conditions are caused by mutations in DNA sensing and signaling?
Fanconi anemia (FA) and ataxia-telangiectasia (AT)
What 1 condition is caused by mutations in DNA topology?
Bloom syndrome (BS)
What 4 conditions are caused by mutations in DNA repair?
Xeroderma pigmentosum (XP), Cockayne syndrome (CS), Trichothiodystrophy (TTD), and hereditary non-polyposis colon cancer (HNPCC/Lynch’s Syndrome)
What do HDAC inhibitors do?
Inhibit HDAC activity, increasing histone acetylation and gene transcription
What do DNMT inhibitors do?
Block activity of DNMTs, decreasing histone methylation, increasing gene transcription
