Untitled Flashcards Set
Please provide the context or sentence fragment for me to assist you with an autocomplete response.P53: a crucial tumor suppressor involved in DNA repair, cell cycle regulation, and apoptosis, short lived protein, most common in cancer, is a transcription factor
Li Fraumeni Syndrome: rare p53 inherited disorder, mutations in tp53 which codes for p53
SV40 Large T Antigen: Specific protein is expressed in SV40 transformed cells=SV40 large T- antigen located in the nucleus, responsible for transforming cells. It can induce cells to become cancerous. It does this primarily by disrupting key cellular regulatory pathways, especially those involving the tumor suppressor proteins p53 and retinoblastoma protein (Rb).
Missense mutation: majority of p53 mutations,
Nonsense mutation
Frameshift mutation
Transactivation domain: The p53 protein has a transactivation domain that enables it to activate genes involved in DNA repair, cell cycle arrest, and apoptosis in response to DNA damage. Mutations that affect this domain (e.g., in Li-Fraumeni syndrome) can impair p53’s ability to control cell growth and prevent tumor formation - 1st domain
Sequence-specific DNA binding domain: Hot spot for oncogenic p53 mutations, MOST MUTATIONS located there - 2nd domain
Tetramerization domain: p53 functions as a tetramer - 3rd domain
Dominant negative: mutation in one locus of p53 act as a dominant negative at the molecular level
MDM2: aka mouse double minute 2 - negative feedback
MDM2 binds directly to the p53 protein, blocking its transactivation domain, which prevents p53 from activating genes by tagging p53 with ubiquitin
p53, in turn, can activate the transcription of the MDM2 gene, creating a negative feedback loop
DNA damage: caused by UV radiation, ionizing radiation, oncogene signaling
ATM: ATM (Ataxia-Telangiectasia Mutated) is a protein kinase that plays a crucial role in the cellular response to DNA damage, particularly double-strand breaks
P21: inhibitor of CDK, DNA polymerase
ARF: (Alternative reading frame): second mechanism to regulate p53 activity. inhibits MDM2 activity
Ink4A-Arf locus: encodes two proteins—
p16^INK4a (Rb pathway): inhibits cyclin-dependent kinases CDK4 and CDK6
p14^ARF (p53 pathway): interacts with MDM2, a protein that promotes the degradation of p53. By binding to MDM2, p14^ARF stabilizes and protects p53 from degradation
inactivates tumor suppressive pathways involving both Rb and p53
E1A: oncogenic signal; forces the host cell to enter the S phase (DNA synthesis phase) of the cell cycle by disrupting rb, inhibits rb
Apoptosis: irreversible cell death; triggered by p53
Phagocytic cell (eg. macrophage): Phagocytic cells like macrophages and dendritic cells recognize and engulf the cell fragments. The phagocytic cells secrete cytokines that inhibit inflammation.
Necrosis: Response to mechanical damage, infection, inflammation. Clumping and random degradation of DNA. Swelling and rupture of cell membrane. Cell content leaks out. Accidental, worse than apoptosis
Inflammation:
Extrinsic apoptosis pathway: Death ligand binding to the death receptor, DISC formation, caspase activation 8,10,3,6,-7 apoptosis
Death ligand (FASL): binds to death receptors
Death receptor (FAS): Fas is the receptor that binds FasL and transduces the apoptotic signal into the cell, initiating the extrinsic apoptosis pathway.
Caspases: have cysteines at their active site
Initiator: caspase 8,9, 10
Executioner: 3,6,7 - cleaves lamin and actin
Inflammatory: 1, 5, 11
Pro-caspases:
Initiator: pro-caspase-8, pro-caspase-9) have long pro-domains that contain specific motifs allowing them to interact w
Lamin: chromatin condensation, nuclear shrinkage
Actin: pro-caspase-3, pro-caspase-7) lack these long pro-domains. They are activated by cleavage by upstream initiator caspases rather than by complex formation, blebbing
Membrane blebbing: during apoptosis
ICAD: Inhibitor of Caspase-Activated DNase): release of endonuclease (CAD/DFF40) which fragments DNA, results in DNA laddering Cellular Substrates cleaved by executioner caspases during apoptosis and consequences
DNase/endonuclease: enzymes cleaved DNA molecules
DNA laddering:
Initiator procaspase:
Caspase-8, -10
Executioner procaspase
Caspase-3, -6, and -7
Intrinsic (mitochondrial) apoptotic pathway: Triggered by extra and intracellular stresses, eg. DNA damage, oncogene deregulation. Leads to reduced mitochondrial integrity (release of cytochrome C)
Cytochrome C: small heme-containing protein that plays a crucial role in cellular energy production and, in the context of apoptosis the mitochondria release cytochrome c, which then combines with apoptotic protease activating factor 1 (Apaf-1) and caspase-9 to form the apoptosome, a complex often described as a "7-spoked wheel of death.
BCL-2: Inhibition of intrinsic pathway induction
BCL-2 family:
BAX, PUMA, NOXA: BAX, PUMA, and NOXA are members of the BCL-2 protein family and play critical roles in promoting apoptosis through the mitochondrial (intrinsic) pathway.
APAF1: (Apoptotic Protease-Activating Factor 1) is a critical protein involved in the intrinsic (mitochondrial) pathway of apoptosis. It plays a key role in the activation of caspase-9, which is one of the initiator caspases in the apoptotic cascade
Apoptosome “wheel of death”: cascade 9, crystal structure, 7 spokes, cytochrome c’s are at the end of apoptosomes, at the dome you have caspase 9.
Immortalization: proliferating without limits
Senescence: a state in which a cell loses its ability to divide and proliferate, while remaining metabolically active; a result of telomere shortening over time. GROWTH ARREST - not deat
“End replication problem”: The end replication problem is a challenge during DNA replication where the very ends of linear chromosomes (telomeres) cannot be fully replicated, leading to telomere shortening. This problem is mitigated by telomerase, which replenishes the telomere sequences, and the shelterin complex
RNA primer for DNA synthesis: RNA primer is synthesized first, allowing DNA polymerase to begin adding DNA nucleotides.
Herman Muller;: proposed the ends of the chromosomes
The discovery that exposing maize to X-rays caused DNA breaks and chromosome fusions, while certain ends of chromosomes seemed to resist fusion, was made by Barbara McClintock in the 1930s
Telomere: end of chromosome; gt rich strand, not active in somatic but active in germline and stem
T-loop: formed by a single-stranded overhang at the end of the telomere, which is folded back and invades the double-stranded telomeric region.
TRF1 and TRF2: TRF1 binds to the double-stranded region of the telomere, specifically to the telomeric repeats (TTAGGG in humans). This helps to form a protective cap at the end of the chromosome. TRF2 plays a key role in maintaining the T-loop structure, which is essential for protecting the chromosome ends. TRF2 facilitates the formation and stabilization of this loop by promoting the invasion of the single-stranded telomeric overhang into the double-stranded telomeric region, forming the T-loop.
Titia de Lange: identified proteins associated with telomeres named TRF
POT1: protector of telomeres – binds to single strand DNA that comes off the t loop
Tetrahymena—micro and macronucleus: micronucleus breaks down genes find in macronucleus with the ends
Carol Greider: used ciliate to examine the tetrahymena with Elizabeth Blackburn and discovered telomerase through banding
Telomerase: is an enzyme that adds repetitive DNA sequences to the ends of chromosomes (telomeres), counteracting telomere shortening during cell division., activate in 90% of cancers
hTERT = human telomerase reverse transcriptase: taking RNA as a template and using it to synthesize DNA, catalytic subunit of telomerase, responsible for adding repetitive telomeric DNA sequences to the ends of chromosomes, thereby maintaining telomere length.
hTR = human telomerase RNA: serve as the RNA template
mouse telomere length
telomerase knock out mouse: TERC knockout mice lack the RNA component of the telomerase complex, which is required for the enzyme's ability to extend telomeres, more susceptible if you get rid of telomerase in the germ cells
Crisis: cells slip through senescence and start dying instead
Breakage-fusion-bridge (BFB) cycle: chromosome breaks lead to the fusion of chromosome ends, followed by the formation of chromosomal bridges during mitosis.
Jerry Shay: discovered oligo therapy and targets catalytic activity:
Imetelstat: inhibits telomerase by binding to the RNA component of telomerase (hTR)
ALT: Alternative Lengthening of Telomeres: uses homologous recombination to elongate telomeres in the absence of telomerase
Gene conversion: non-reciprocal genetic exchange that occurs during homologous recombination.
Multi-step tumorigenesis: initiation, promotion, progression of mutations
Population doubling: doubling time of a tumor
Polyp: precursor to cancer; abnormal growth of tissue that typically protrudes from a mucous membrane, often found in organs such as the colon, stomach, nose, or uterus.
Polypectomy: Polypectomy is a medical procedure used to remove polyps
FAP: germline APC mutation
APC: Adenomatous Polyposis Coli; APC is a central regulator of the Wnt signaling pathway, which controls the levels of β-catenin, a protein involved in cell adhesion and gene transcription.
KRAS: is a gene that encodes a small GTPase protein involved in regulating various cellular processes, including cell growth, differentiation, survival, and apoptosis
SMADs: intracellular signal transducers that play a crucial role in the TGF-β (Transforming Growth Factor-beta) signaling pathway
Stem cells: that have the ability to self-renew (make copies of themselves) and differentiate into various types of specialized cells
Independent events/”hits”/ mutations: single mutation
Driver mutation: A mutation that directly contributes to cancer by conferring a growth advantage to the cell- u only need 6
Passenger mutation: mutation that does not contribute to cancer development directly but occurs as a byproduct of the cancerous proces
Adenovirus E1A: The E1A gene in adenovirus encodes a protein that can inactivate tumor suppressors like Rb and activate cellular transcription factors involved in cell cycle progression. E1A is often used in research to induce cell cycle re-entry and transformation.
SV40 small T Antigen: viral protein that interacts with protein phosphatase 2A (PP2A), which regulates cellular signal transduction
DNA polymerase: enzyme responsible for synthesizing new DNA strands by adding nucleotides to the growing chain. Has 3’ 5’ exonuclease activity. This function allows the polymerase to "backtrack" and correct errors during replication.
HNPCC/Lynch Syndrome: Lynch Syndrome, is a genetic condition that increases the risk of colorectal cancer and other cancers due to defects in mismatch repair (MMR) genes. Characterized by multiple colon cancers at an early age. Even though the name has nonpolyposis in it, people with HNPCC will still develop a small number of polyps as a precursor to colon cancer. Mutations in mismatch repair genes (human Mut L and S homologs) are related to this syndrome. People who have inherited this condition are also at increased risk for a number of other types of cancers including uterine, ovarian, endometrial, and stomach.
hMLH1/Mut L: Part of the MutL complex involved in identifying and repairing errors during DNA replication.
hMSH2/Mut S: Part of the MutS complex, responsible for recognizing and binding to mismatched base pairs in the DNA.
Mismatch repair (MMR): a system for detecting and repairing errors (mismatched base pairs) that occur during DNA replication
Double strand DNA breaks (dsDNA breaks): are severe forms of DNA damage where both strands of the DNA helix are broken. These are highly mutagenic and require specialized repair pathways to maintain genomic integrity.
Ionizing radiation: causing dsDNA breaks through xrays
Homology directed repair (HDR): is a high-fidelity DNA repair mechanism that fixes double-strand breaks using an intact homologous template, often a sister chromatid, to restore the original DNA sequence.
BRCA1 BRCA2: BRCA1 and BRCA2 are key proteins involved in HDR and the repair of double-strand DNA breaks. Mutations in these genes significantly increase the risk of breast and ovarian cancers.
RAD51: A protein that aids in strand invasion during HDR, helping to repair breaks by using a homologous template
ATM: A protein kinase that detects DNA damage (e.g., DSBs) and activates repair mechanisms like BRCA1/BRCA2.
Mary Claire King: discovered BRCA1
Sister chromatid: one of the two identical copies of a chromosome that are formed during DNA replication. They are joined together at the centromere and are separated during cell division.
5’ 3’ exonuclease: Used in DNA repair (removes damaged bases or primers).
Nonhomologous End Joining (NHEJ): DNA repair pathway that fixes double-strand breaks without requiring a homologous template. It is error-prone and can lead to small insertions or deletions (indels) at the break site. In the G1 phase, DNA damage caused by X-rays is primarily repaired through NHEJ, while POT1 and p53 are involved in regulating DNA repair and protecting telomeric DNA.
Errors in DNA replication: mismatched bases, stutter, double stranded breaks
Endogenous biochemical processes (know that this can be a cause of DNA mutations): oxidation, depurination, methylation, deamination
Physical mutagen: ionizing radiation (X-rays, gamma rays) and UV light, which cause physical damage to DNA, such as double-strand breaks or pyrimidine dimers
X-Ray: examples of physical mutagens that can cause DNA damage. UV radiation in particular is known for inducing pyrimidine dimers, which are formed when two adjacent pyrimidine bases (typically thymine) bond to each other due to UV irradiation. These dimers distort the DNA structure and are a source of mutations.
Nucleotide Excision Repair (NER): DNA repair mechanism that removes bulky DNA lesions (e.g., pyrimidine dimers) caused by UV light.
Xeroderma Pigmentosum (XP): is a genetic disorder caused by defects in the NER pathway, leading to increased sensitivity to UV light and a higher risk of skin cancers.
XPC and XPE: Recognize and bind to damaged DNA
XPB and XPD: Helicases that help unwind the DNA around the lesion.
XPF and XPG: Endonucleases that excise the damaged DNA
DNA polymerase (epsilon): is involved in leading strand synthesis during DNA replication and has proofreading abilities with 3’–5’ exonuclease activity
Error-free bypass: is a process where DNA polymerase bypasses DNA damage without introducing mutations. This can occur through specialized polymerases like pol delta or pol epsilon.
DNA polymerase (eta): XPV, automatically puts A-A in the new strand across from a pyrimidine dimer. In error-prone bypass of pyrimidine dimers,
Error-prone bypass: DNA polymerases replicate across a region of DNA that contains damage, such as pyrimidine dimers (formed by UV light), without accurately repairing the damag
DNA polymerase (zeta): places a random nucleotide in the newly synthesized DNA strand across from the damaged region.
Alkylation: refers to the addition of an alkyl group (e.g., methyl or ethyl) to DNA bases, which can lead to DNA distortion and mutation
MGMT (O6-methylguanine-DNA methyltransferase): is a DNA repair protein that removes alkyl groups from the O6 position of guanine, preventing mutations and cancer. Loss of MGMT function is associated with increased susceptibility to alkylating agents. directly reverse alkylation of methylated guanine and is transcriptionally repressed in some cancers.
Base Excision Repair (BER): fixes small, non-helix-distorting lesions, such as those caused by oxidative damage or alkylation. The damaged base is excised and replaced with the correct base.
APE: Apurinic/apyrimidinic endonuclease cleaves backbone, removes sugar phosphate
. Mdm2 and p53 are both phosphorylated by ATM in a cell that has experienced DNA damage