Oncogenic Viruses, DNA Repair, Cancer & Cell Signaling Review

Flashcards covering commonalities of oncogenic DNA viruses, H. pylori effects, breast cancer risks, estrogen mechanisms, DNA enzymes, repair mechanisms (one-step, BER, NER, MMR, recombinational), defects in repair, chemotherapy functions, DNA-binding domains, cancer and transcriptional control, DNA methylation, histone modification, lncRNA, miRNA, dicer, telomeres, telomere shortening, telomerase, EGFR growth signaling, and associated proteins (SH2, SH3, GRB, SOS, RAS, AP-1, SRC, MYC MAX).

What are the commonalities of oncogenic DNA viruses?

They integrate into the host genome and involve oncoproteins.

What are the effects of H. pylori causing chronic infections?

It leads to inflammation mediated by epithelial cell release of ROS and RNOS, as well as IL-8 and Gro-a, causing oxidative damage to DNA via guanine-to-thymine transversions.

What percentage of all stomach cancers are caused by H. pylori?

H. pylori causes over 60% of all stomach cancers, specifically gastric adenocarcinomas.

How does obesity increase the risk of breast cancer?

Adipose tissue produces aromatase, which converts androgens into estrogens, thereby increasing estrogen exposure.

What are aromatase inhibitors designed to do?

They target the enzyme aromatase, reducing estrogen levels, especially in post-menopausal women.

List several factors that increase the risk of breast cancer.

Obesity, alcohol consumption, late menopause, early menarche, first pregnancy after age 30, oral contraception, and hormone replacement therapy.

How do estrogens promote cell proliferation in the breast?

They promote cell proliferation with a rate-related increase of errors in DNA going unrepaired, leading to mutations.

How does estradiol metabolism impact DNA?

Estradiol is metabolized to form estradiol-3,4-quinone, which binds DNA, producing adducts that destabilize DNA.

What is the function of endonucleases in DNA?

Endonucleases cut the DNA strand in the middle.

What is the function of exonucleases in DNA?

Exonucleases cut the DNA strand at the end.

What is the function of DNA polymerases?

DNA polymerases synthesize DNA.

What is the function of ligases in DNA repair?

Ligases join DNA gaps.

What is the function of glycosylases in DNA repair?

Glycosylases remove damaged nitrogenous bases.

What is the primary function of one-step DNA repair?

It involves the direct reversal of DNA damage, mediated by alkyltransferases, to remove alkyl groups and restore guanine structure, repairing O6 guanine derivatives.

What type of DNA damage does Base Excision Repair (BER) primarily target?

BER targets base lesions occurring from oxidation, deamination, and alkylation.

What is the difference between short-patch and long-patch BER?

Short-patch BER generally generates a gap of 1 nucleotide, while long-patch BER generates a gap of 2-10 nucleotides and is predominant in proliferating cells.

What is the first step in Base Excision Repair (BER)?

The first step is mediated by DNA damage-specific glycosylases, such as MUTYH, which scans for lesions like mismatched adenines paired with 8-oxoguanine.

What type of DNA lesions does Nucleotide Excision Repair (NER) primarily address?

NER handles helix-distorting lesions such as pyrimidine dimers induced by UVB and bulky DNA adducts induced by PAHs.

What is the role of Xeroderma pigmentosum (XP) complementation group proteins in NER?

These proteins are involved in the recognition of DNA damage during NER.

What is the primary function of Mismatch Repair (MMR)?

MMR corrects replication errors that escaped polymerase editing, particularly slippage during replication of repetitive sequences.

How does the mismatch repair system discriminate between daughter and template strands?

The system flags the daughter strand to identify the incorrect nucleotide.

What type of DNA breaks does Recombinational Repair mend?

Recombinational repair mends double-strand DNA breaks.

What kinase is activated in response to double-strand DNA breaks during recombinational repair?

Ataxia telangiectasia mutated (ATM) kinase is activated.

What is MUTYH-associated polyposis syndrome (MAP) caused by?

MAP is caused by inherited defects in BER due to MUTYH gene mutations, leading to multiple colorectal adenomas.

What is Xeroderma Pigmentosum (XP) and what is its main characteristic?

XP is an inherited disorder characterized by a defect in NER, resulting in hypersensitivity to the sun and a 1000-fold increase in skin cancer risk.

How do alkylating agents and platinum-based chemotherapy drugs work?

They produce DNA adducts by forming covalent bonds (alkyl groups or platinum atoms) and cross-links that prevent DNA separation, mainly targeting the N7 position of guanine or adenine, ultimately triggering apoptosis.

How do antimetabolite chemotherapy drugs function?

They are structurally similar to nitrogenous bases, mimicking endogenous molecules and inhibiting nucleic acid synthesis.

How do f-dUMP and methotrexate, as cancer drugs, impact DNA synthesis?

f-dUMP competes with dUMP for a binding site, inactivating thymidylate synthase, while methotrexate competes with dihydrofolate and inhibits dihydrofolate reductase, both compromising DNA synthesis.

How does Doxorubicin, an organic chemotherapy drug, work?

Doxorubicin inhibits topoisomerase, forms DNA adducts, and intercalates into DNA.

What are DNA-binding domains?

They are protein confirmations that enable transcription factors to bind DNA.

List some common DNA-binding domain motifs.

Helix-turn-helix, leucine zipper, helix-loop-helix, and zinc finger.

How do mutations that activate transcription factors contribute to cancer?

They increase the binding of transcription factors to the promoter and enhance the transcriptional activation of genes.

What is the effect of DNA methylation on cytosine nucleotides?

Methylation of cytosine nucleotides 5' to guanine nucleotides (CpGs) can result in cytosine-to-thymine transitions.

What is the role of DNA methyltransferases (DNMTs)?

DNMTs mediate the methylation of cytosine nucleotides.

How does gene silencing due to methylation relate to carcinogenesis?

Abnormal gene silencing, such as the loss of estrogen receptor protein in ovarian cancer or BRCA1 in inherited breast cancer, is an important mechanism in carcinogenesis.

What is the effect of hypomethylation in cancer cells?

Cancer cells may exhibit hypomethylation, leading to the activation of genes not normally expressed, including oncogenes, genes involved in metastasis, and transposable elements causing gene rearrangements.

What altered enzymes are associated with histone modification in cancer?

Histone deacetylases (HDACs) and histone acetyltransferases (HATs) are often altered.

How does the PML-RAR fusion gene in promyelocytic leukemia affect gene expression?

The fusion protein recruits HDACs to gene promoter regions, repressing gene expression and blocking cell differentiation.

What are lncRNAs and their function?

LncRNAs are endogenous RNAs longer than 200 nucleotides, transcribed from gene enhancers, playing a role in gene expression, epigenetic modifications, and linked to p53 effects.

How is PCA3 utilized in prostate cancer diagnostics?

It is strongly overexpressed in over 95% of primary prostate cancer samples (not expressed in healthy tissues) and is an FDA-approved RNA-based urine test for prostate cancer diagnosis.

What are miRNAs and how do they regulate gene expression?

MiRNAs are non-protein coding RNAs that regulate mRNA expression. Pre-miRNAs are cleaved by dicer to produce double-stranded miRNAs, which then separate, and mature single strands combine with RISC to degrade target mRNA.

What are telomeres and what is their primary function?

Telomeres are repetitive DNA sequences and specialized proteins at the ends of chromosomes that protect chromosome ends from enzymatic digestion and prevent DNA double-strand break repair.

What happens to chromosomes during each round of replication?

Chromosomes progressively erode and shorten during each round of replication.

What causes chromosome shortening after DNA replication?

It is due to the end-replication problem, a limit of DNA polymerase that requires an RNA primer, which, once removed from the 5' ends, leaves gaps that cannot be filled, leading to progressive shortening.

What is the consequence when chromosomes reach a critically short threshold length?

Cells enter a stable and irreversible state of growth arrest called senescence, or if critically short, can lead to apoptosis or transformation.

What is telomerase and what does it do?

Telomerase is a ribonucleoprotein containing human telomerase reverse transcriptase (TERT) and human telomerase RNA (hTR) that maintains telomere length by synthesizing DNA from the hTR template to add new repeats and extend the telomere.

What is the primary function of kinases in growth signaling?

Kinases catalyze the transfer of a phosphate group from ATP or GTP to a hydroxyl group on specific amino acids in a target protein.

What are the three receptor protein domains of EGFR (Epidermal Growth Factor Receptor)?

The extracellular ligand-binding domain, the transmembrane domain, and the cytoplasmic protein tyrosine kinase domain.

What is the first step in the EGFR growth signaling cascade?

EGF (the ligand) binds to a binding pocket of the EGFR, activating the dimerization domain and causing a conformational change.

What happens after EGFR dimerization in the growth signaling cascade?

Dimerization results in autophosphorylation of both kinase domains, making ATP available for energy transfer and allowing cytoplasmic proteins to be recruited, transducing the signal inside the cell.

List the sequential steps of signal transduction in growth factor signaling.

Binding of the growth factor, receptor dimerization, autophosphorylation, recruitment of proteins with SH2 domains, activation of intracellular transducers (including RAS), activation of a serine/threonine kinase cascade (RAF-MEK-MAPK), and regulation of transcription factors for gene expression.

What does RAS-GTP recruit and activate in the growth signaling pathway?

RAS-GTP recruits, binds to, and activates RAF (a serine/threonine kinase).

What is the role of activated RAF?

Activated RAF acts as a signal transducer, initiating a cascade of phosphorylation by phosphorylating and activating MEK (MAPK/ERK kinase).

What does activated MAPK do in the cell?

Activated MAPK enters the nucleus, phosphorylates, and activates transcription factors that turn on specific sets of genes needed for cell growth.

What are the mechanisms for the termination of kinase activity in growth signaling?

Mechanisms include additional phosphorylation that inhibits ligand binding and kinase activity, dephosphorylation by phosphatases, binding of negative regulators to the kinase domain, and receptor endocytosis and degradation.

What roles do SH2 and SH3 domains play in growth signaling?

These domains mediate protein-protein interactions by creating high-affinity binding sites for proteins on phosphorylated tyrosine residues, such as GRB2, SRC, ABL, and PI3K.

What is the function of GRB2 in growth signaling?

GRB2 is an intracellular adapter protein that recognizes phosphorylated EGF receptors and facilitates the recruitment of specific proteins, like SOS (son of sevenless), to the membrane, which enables the activation of membrane-bound intracellular transducer RAS.

What is the role of SOS (son of sevenless) in the RAS pathway?

SOS is a RAS guanine nucleotide exchange factor (GEF) that is translocated from the cytoplasm to the membrane in response to growth factor stimulation, mediating the exchange of GDP for GTP to activate RAS.

What is the primary function of RAS proteins in growth signaling?

RAS proteins are pivotal intracellular transducers that integrate growth factor signals initiating from the membrane, acting as binary ON/OFF switches (inactive when bound to GDP, active when bound to GTP).

Which RAS family member is commonly mutated in cancers?

K-RAS is a commonly mutated gene in cancers.

What is AP-1 and what does it regulate?

AP-1 is an important target of the MAPK cascade that binds DNA, activates the cyclin D gene (a critical cell cycle regulator), and regulates the expression of genes involved in growth, differentiation, and death.

What is the primary effect of SRC activation in cell adhesion and motility?

Activation of SRC, an intracellular tyrosine kinase, results in reduced cell adhesion and increased cell motility by facilitating the disassembly of focal adhesions.

What is the function of the MYC protein?

MYC is a short-lived protein that promotes proliferation by regulating the expression of specific target genes and requires the constitutively expressed family member MAX to function.

How do MYC and MAX interact to produce their effects?

MYC and MAX form heterodimers and bind DNA, which is critical for the oncogenic, mitogenic, and apoptotic effects of MYC.