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Test 3 Flashcards

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1
Q

Cyclin complexes that operate through the animal cell cycle

A

Cdk1/CycB are not the only cyclin complex active throughout cell cycle

Cdk4,6/CycD complex mediates transition through restriction point

Cdk2/CycE complex mediates transition from G1 to S phase

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2
Q

Name the steps to mitosis

A

Prophase
prometaphase
metaphase
anaphase
telophase
cytokinesis

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3
Q

What is Immunofluorescence?

A

Use antibodies to visualize the presence of proteins and other molecules in cells and tissue, usually through a fluorescent molecule (immunofluorescence) or an enzymatic reporter bound to an antibody.

Can be used in conjunction with fluorescent stains like DAPI (stains DNA)

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4
Q

What allows us to target multiple antigens in the same sample?

A

Double or multicolored labelling

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5
Q

What triggers changes in cellular organelles and mitotic structures?

A

Mitotic kinases

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6
Q

Describe how Mitotic kinases trigger changes in cellular organelles and mitotic structures

A

MPF/Cyclin B-Cdk1 activates other mitotic protein kinases like Aurora kinase

Aurora kinase then phosphorylates and activates Polo-like kinase

These kinases function in a positive feedback loop and play multiple roles during mitosis

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7
Q

What organizes sister chromatids as they progressively condense through the cell cycle?

A

Condensin and cohesins

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8
Q

Describe how Condensin and cohesins organize sister chromatids as they progressively condense through the cell cycle

A

Cohesin binds DNA during S phase, maintain linkages between sister chromatids during DNA replication

Condensins are activated and replace cohesins, cohesins only found near centromere

Condensins drive chromatin condensation by forming DNA loops

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9
Q

What is one of the triggering events of prophase?

A

CDK1 phosphorylation of nuclear lamins

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10
Q

Describe CDK1 phosphorylation of nuclear lamins

A

Phosphorylation of nuclear lamins by Cdk1/cyclin B  dissociation of lamina polymers into free lamin dimers

Integral nuclear envelope proteins are absorbed into ER, which will be distributed to daughter cells

Golgi also breaks into small vesicles that are absorbed into ER or distributed to daughter cells

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11
Q

Describe the mitotic spindle

A

The mitotic spindle is composed of microtubules. These microtubules attach to and reposition chromosomes during mitosis

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12
Q

How is the movement of spindle poles mediated?

A

By molecular motors – kinesins (+) and dyneins (-)

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13
Q

What are the different components of the mitotic spindle?

A

Interpolar microtubules
astral microtubules
kinectocore microtubules

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14
Q

What is a kinectocore? What are some of its functions?

A

Dense protein complex associated with centromeres that serves as attachment site of kinetochore microtubules

The kinetochore also senses tension from attached microtubules and regulates progression through mitosis

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15
Q

What do spindle microtubules do?

A

“search and capture” the kinetochore through an intrinsic property called dynamic instability

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16
Q

What is the metaphase plate?

A

The region in the middle of the cell between both spindle poles where chromosomes align during metaphase

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17
Q

Describe the spindle assembly checkpoint

A

APC/C activity is blocked by mitotic checkpoint complex (MCC), which is assembled through the activity of unattached kinetochores

Kinetochore attachment to spindle fibers inhibits MCC formation, leading to APC/C ubiquitinating both the MPF (specifically cyclin B) and securin, an inhibitory subunit of separase

Separase then degrades cohesin, separating sister chromatids leading to the initiation of anaphase

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18
Q

What are the forces that separate chromosomes on the spindle? Describe them.

A

Astral microtubules pull spindles towards the plasma membrane

Interpolar microtubules slide past one another, pushing spindles apart

Kinesins associated with kinetochores depolymerize kinetochore microtubules, shortening them, leading to chromosomes being “pulled” towards spindles

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19
Q

Describe Anaphase

A

Inactivation of Cdk1(through proteasomal breakdown of cyclin B) leads to chromosome decondensation and cytokinesis

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20
Q

What does cytokinesis involve?

A

the formation of a contractile actin ring, the cytokinetic furrow

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21
Q

Cytokinesis initiates following what?

A

the inactivation of Cdk1

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22
Q

What is the formation of contractile ring mediated by?

A

Aurora and Polo-like kinases

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23
Q

Describe cytokinesis in plant cells

A

During cytokinesis in plants, vesicles will fuse to form a cell plate, which grows to form plasma membrane between adjacent cells

Cell wall growth follows cell plate extension

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24
Q

What is cancer the result of?

A

uncontrolled cell growth

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25
Q

What is cancer is characterized by?

A

loss of cell cycle regulation, usually resulting from mutations in cell cycle regulatory genes

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26
Q

What is a tumor?

A

Any abnormal proliferation of cells

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27
Q

What is the difference between a benign and malignant tumor?

A

Benign tumors do not spread throughout the body (metastasis) and are confined to a specific area. Their growth can still result in deleterious effects for the individual.

Malignant tumors are capable invading surrounding tissues and metastasizing to other locations in the body.

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28
Q

Why do tumor cells often have abnormal appearances?

A

as a result of the accumulation of mutations.

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29
Q

What are the three main groups of cancers and describe them.

A

Carcinoma - ~90% of human cancers, cancers of epithelial cells

Sarcoma – cancers of connective tissues (muscle, bone, cartilage, fibrous tissues)

Leukemia and lymphoma – cancers of blood-forming cells(leukemias) and immune cells (lymphomas)

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30
Q

What are the three steps to the development of cancer?

A

Tumor initiation, tumor progression, and clonal selection.

The transformation of a healthy cell into a tumor cell is usually a multi-step process resulting for a series of accumulated mutations

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31
Q

Describe tumor initiation

A

mutations cause abnormal proliferation of a single cell – forms a clonal population that ultimately gives rise to a tumor or neoplasm

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32
Q

Describe tumor progression

A

additional mutations accumulate in tumor population of cells – may confer an advantage to tumor cells, such as increased growth/proliferation

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33
Q

Describe clonal selection

A

cells with increased growth/proliferation in tumor population are selected for – their cell lineage becomes dominant cell type in tumor

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34
Q

True or false: Cancer cells often lack properties seen in healthy cells

A

True

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35
Q

What do healthy cells generally exhibit that leads to quiescence? Entering G0 of cell cycle

A

density-dependent inhibition and contact inhibition

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36
Q

What is a characteristic of tumor proliferation?

A

Tumor cells often exhibit proliferation that is not inhibited by contact with other cells or cell density, leading to abnormal cell growth and altered cell migration phenotypes

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37
Q

True or false:

Many tumor cells exhibit increased adhesion to the extracellular matrix, and some secrete proteases to actively degrade extracellular matrix proteins

A

False. Tumors exhibit decreased adhesion to the cellular matrix

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38
Q

What do cancer cells often produce and secrete, and what does this do?

A

Cancer cells often produce and secrete growth factors – which leads to autocrine growth stimulation

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39
Q

What is angiogenesis?

A

Angiogenesis is the process of new blood vessels forming from existing blood vessels, this can make the tumore even more ingrained in your body and these vessels provide nutrients and oxygen to the growing tumor – can also lead to metastasis

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40
Q

What can carcinogens do?

A

introduce mutations that cause cancer

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41
Q

Give examples of carcinogens

A

asbestos, radon, formaldehyde, UV light

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42
Q

Give two examples of tumor viruses

A

human papillomavirus (HPV) and Rous sarcoma virus (RSV)

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43
Q

What is an oncogene?

A

genes capable of inducing cancer

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44
Q

what do oncogenes derive from?

A

Oncogenes derive from mutations in proto-oncogenes – genes that drive cell proliferation

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45
Q

Give an example of a proto-onco gene

A

Viral raf oncogene has regulatory domain replaced by a partially deleted viral domain (Gag), leading to constitutive activity

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46
Q

How were oncogenes first discovered?

A

first identified through studies of tumor viruses

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47
Q

How did we get direct evidence for cellular oncogenes?

A

Through gene transfer.

DNA extracted from human cancer cells was introduced to healthy mouse cells in cell culture.

Mouse cells were transformed into tumor cells, indicating that DNA extracted contained mutated oncogenes

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48
Q

How do oncogenes develop?

A

Develop from proto-oncogenes through mutations.

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49
Q

Describe mutations in ras genes

A

Mutations in ras genes are involved in approximately 30% of all human malignancies, including about 50% of colon and 25% of lung carcinomas

Normal vs. oncogenic forms of ras may differ by as little as a single nucleotide (point mutation)

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50
Q

Describe altered expression of c-myc gene

A

Altered expression of the c-myc proto-oncogene can result from a translocation of c-myc from chromosome 8 to chromosome 14, leading to different regulatory elements controlling the expression of c-myc

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51
Q

True or false:
Many proto-oncogenes function in cell-signaling pathways

A

True

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52
Q

Give examples of proteins involved in growth factor/RTK/MAPK signal transduction pathways that can become oncogenes through mutation.

A

Growth factors
Growth factor receptors (RTKs)
Ras
Raf
Intracellular kinases (MEK, ERK)
Transcription factors (Elk-1, AP-1)

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53
Q

Describe how the Wnt pathway involved proto-onco genes.

A

In the absence of Wnt, Beta-catenin is phosphorylated by destruction complex, targeting it for ubiquitination and degradation (E3 ubiquitin ligase pathway)

Wnt signaling through Frizzled regulates development and cell proliferation through regulation of gene expression

Mutations that prevent Beta-catenin degradation can convert it to an oncogene and lead to increased expression of target genes, including c-myc and Cyclin D1

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54
Q

True or false:
proto-oncogenes cannot regulate apoptosis

A

False

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55
Q

Describe how proto-onco genes can regulate apoptosis

A

Growth factor signaling through RTKs inhibits proapoptotic regulatory proteins like Bad and Bim

Akt also inhibits the proapoptotic FOXO transcription factors

Mutations in PI3K, Akt, or Bcl-2 can cause the cell to fail to undergo apoptosis in response to appropriate signals

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56
Q

How do tumor suppressor genes like Rb function to inhibit cell proliferation?

A

Rb is a repressor of E2F transcription factors which regulate expression of cell-cycle and S phase specific genes

Phosphorylation of Rb by Cdk4,6/Cyclin D complex leads to its dissociation, activating E2F and transcription of target genes

Mutations in Rb can lead to overexpression of cell cycle genes, driving tumor initiation

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57
Q

What is Rb

A

Retinoblastoma protein – first tumor suppressor gene identified

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58
Q

How were tumor suppressor genes hypothesized to exist?

A

Following cell fusion experiments that fused tumor cells and healthy cells

The fused cell was usually nontumorigenic, suggesting that genes present in the healthy cell could suppress tumor development and proliferation

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59
Q

How does Human papillomavirus (HPV) inhibit Rb and drive tumor development?

A

The viral HPV protein E7 binds to and inhibits Rb in HPV infected cells and can drive tumor development through post-translational inactivation of Rb, rather than mutational inactivation

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60
Q

What are the numbers on HPVs cancer rates?

A

HPV causes ~3% of all cancers in women and 2% of all cancers in men, including the majority of cervical cancer and oropharyngeal cancer

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61
Q

What is p53?

A

p53 is another key tumor suppressor gene activated in response to DNA damage.

p53 was the second tumor suppressor gene to be identified

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62
Q

What does p53 do?

A

p53 is phosphorylated and activated in response to DNA damage – induces expression of p21 (cell cycle arrest at G1–>S transition and/or
Bcl-2 family members PUMA and Noxa (apoptosis) depending on level of p53 induction.

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63
Q

How is p53 degradation mediated?

A

mediated by the E3 ubiquitin ligase MDM2, which can function as an oncogene if overexpressed

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64
Q

True or false:
Estimated that 65% of all cancers have mutations in p53 gene

A

False.
50% of cancers have mutations in p53 gene.

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65
Q

How does PTEN regulate cell proliferation?

A

through dephosphorylation of PIP3

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66
Q

What do mutations in PTEN lead to?

A

increased PIP3 levels and increased Akt signaling, inhibiting apoptosis

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67
Q

Describe how PTEN regulates cell proliferation through dephosphorylation of PIP3

A

PI 3-Kinase – often activated following growth factor binding to RTK; can also be activated by GPCR signaling

Phosphorylates PIP2 to PIP3 which acts as second messenger activating mTOR/Akt – regulate cell growth and cell survival (apoptosis)

Dephosphorylation of PIP3 to PIP2 is regulated by PTEN, a lipid phosphatase that acts as a tumor suppressor

Mutations in PTEN can lead to increased PIP3 levels and increased Akt signaling, inhibiting apoptosis

68
Q

Can Tumor suppressors and oncogenes can function in the same pathway?

A

Yes

69
Q

What do stability genes do?

A

maintain integrity of the genome

70
Q

What are two examples of stability genes?

A

BRCA1 and BRCA2

71
Q

How do BRCA1 and BRCA2 maintain genome stability?

A

BRCA1 and BRCA2 act downstream of ATM/Chk2 activation and repair double-stranded breaks in DNA through homologous recombination. Mutations in BRCA1 and BRCA2 are associated with increased rates of mutation.

72
Q

The viral Human Papillomavirus (HPV) protein E7 can bind to and inhibit the tumor suppressor gene ____________ to drive tumor development

A

Rb

73
Q

What does the progression of tumor development result from?

A

usually results from multiple mutations accumulating in oncogenes and tumor suppressor genes

74
Q

Are some genes more commonly mutated than others to cause cancer? roughly how many genes are commonly mutated to cause cancer?

A

P53 and PI3K are more commonly mutated than others.

~150 genes are commonly mutated and contribute to tumor development

75
Q

What does the accumulation of mutations lead to?

A

A progressive loss of cell cycle regulation and uncontrolled proliferation

76
Q

What is associated with a better cancer outcome?

A

Early detection!
Screening can increase likelihood of identifying cancer early.

77
Q

What can genetic testing do for cancer detection?

A

Genetic testing can identify individuals with mutations in cancer-causing genes (ex. BRCA1/2) who are at higher risk.

78
Q

True or false:
Many drugs exist that target specific oncogenes

A

True

79
Q

Give two examples of cancer immunotherapies

A

Checkpoint inhibitors: PD-1 – programmed cell death protein 1, inhibits T-cell activation when bound to PD-L1 or PD-L2.
Immune checkpoint inhibitors block this interaction.

CAR-T: chimeric antigen receptor T-cell

80
Q

What are the three types of filaments in animal cells?

A
  1. Actin
  2. Microtubules
  3. Intermediate filaments
81
Q

What is the rough diamter of an actin filament?

A

7nm

82
Q

True or false:
Actin is not highly conserved

A

False:
Actin is highly conserved – yeast actin is 90% identical to human actin at AA level

83
Q

Describe how actin can form a polar filament.

A

Actin is a polar molecule that can oligomerize into polar filaments.

G actin – globular or monomeric actin
Assemble into dimers and trimers through head to tail interactions

Trimer represents a “seed”, nucleates actin filament

F actin – filamentous actin – helical structure

Actin has innate ATPase activity that regulates assembly and disassembly

84
Q

Describe how actin’s ATPase ability regulates the assembly and disassembly of filaments

A

ADP-actin is less tightly bound and dissociates from the minus end

Actin bound to ATP (ATP-actin) rapidly associates with growing plus ends

ATP is hydrolyzed to ADP after ATP-actin is incorporated into filament

85
Q

What is “treadmilling”?

A

ATP-actin added to plus end while ADP-actin dissociates from minus end

86
Q

What are the accessory proteins that facilitate ATPase cycle and nucleation of actin?

A

Actin is able to form filaments innately, but filaments are regulated in the cell by accessory proteins

Formin – nucleates new actin filaments (formation of trimer)

Profilin – swaps ADP for ATP on actin monomers, exchange factor

87
Q

What does the Arp2/3 complex do?

A

Arp2/3 – Actin related protein 2/3 – nucleates new actin filaments that branch off of existing filaments – creates branched actin structures

88
Q

Where does the Arp2/3 complex bind?

A

Binds near intersection of ADP-actin and ATP-actin near plus end of filament

89
Q

T/F:
A number of unique actin structures exist in cells

A

True

90
Q

What do sheets of branched actin create?

A

lamellipodia

91
Q

Describe how a series of proteins prevent assembly, disassembly, and motor access of actin

A

Plus end capping protein: Prevent further polymerization/extension of filament

Minus end capping protein: Prevent further depolymerization of filament

Tropomyosin: Stabilize actin filament and block access of molecular motors to actin filament

92
Q

What is cofilin?

A

Cofilin is a filament severing enzyme which can increase polymerization and depolymerization.

severs actin filaments, creating new plus and minus ends that can grow/depolymerize

93
Q

What do actin filaments assemble into?

A

Depending on the type of associated cross-linking protein, actin filaments assemble into:

parallel bundles
mesh-like networks

94
Q

What is the actin cortex?

A

A meshwork of actin that is cross linked and associated with the plasma membrane

95
Q

What is spectrin?

A

actin binding protein that also binds to phospholipids in plasma membrane – made of two polypeptide chains with actin binding domains (ABD) at each end

Provides structural rigidity to cell/maintain cellular morphology

96
Q

What is Ankryn?

A

binds to both spectrin and transmembrane protein band 3 – links spectrin-actin network to plasma membrane

97
Q

What are two examples of bundled actin arrays?

A

Filopodia and stress fibers

98
Q

How is the extracellular environment linked with the actin cytoskeleton (stress fibers)?

A

Stress fibers – tropomyosin stabilized actin filaments crosslinked to alpha actinin, help to anchor cell to substrate/ECM

Stress fibers attach to integrins through the binding of talin and vinculin at sites called focal adhesions

This linkage provides adhesion to the ECM helps create traction force

99
Q

T/F:
Focal adhesion remodel during cell migration

A

True

100
Q

What is actin polymerization controlled by? Describe the process.

A

Rho Family GTPase activity.

Rho activates Arp2/3 and formin to initiate new filaments as well as new branched filaments

Profilin promotes the exchange of ATP for ADP to extend filaments

Cofilin cleaves existing filaments to generate new plus ends

These growing actin filaments push (physical force) against the plasma membrane at the leading edge to drive cell motility

101
Q

Describe how Cell-cell adhesions also link the actin cytoskeleton to adherens junctions

A

Adherens junctions – cell-cell junctions that link to actin filaments on the cytoplasmic face - mediates cell-cell adhesion

Form a continuous belt-like structure around certain cells known as an adhesion belt

Contact is mediated through transmembrane cadherin proteins that extend into the extracellular space and bind intracellular catenins

102
Q

What are microvilli?

A

Microvilli – “small hairs” – small fingerlike cellular protrusions

Abundant in epithelial cells, greatly increase surface area

103
Q

How are microvilli supported?

A

Microvilli are supported by parallel actin fibers linked together by villin and fimbrin

Microvilli are anchored to the actin cortex at a region called the terminal web

104
Q

Give three cell surface projections that all rely on the remodeling of actin filaments

A
  1. Pseudopodia – moderate width cellular extensions involved in phagocytosis and motility
  2. Lamellipodia – broad, sheetlike extensions at the leading edge
  3. Filipodia – thin projections that grow out of lamellipodia
105
Q

Describe the composition of a muscle fiber

A

Muscle fibers are long, multinucleate cells that fuse together during development

Composed of myofibrils – bundles of actin and myosin filaments organized in chains of contractile units known as sarcomeres

106
Q

How does muscle contraction occur?

A

Through highly organized and coordinated motor movement along actin.

Actin fibers sliding past myosin filaments, contracting the sarcomere, forms the basis of the sliding filament model

107
Q

What type of myosin is present in muscle cells?

A

Myosin II. Globular head region binds to actin and hydrolyzes ATP

108
Q

Describe how myosin arrays on a single muscle fiber

A

Multiple actin-myosin contact points along the muscle fiber prevent actin filaments from sliding back as myosin head groups dissociate/reassociate with different sites along the actin filament

109
Q

Describe the contraction cycle of muscles.

A

ATP binding to myosin head group dissociates myosin from actin

ATP hydrolysis induces a conformational change in myosin, moving head group into “cocked” position (myosin still bound to ADP and Pi)

Myosin head group binds to new position on actin filament. Pi is released, initiating “power stroke”

“Power stroke” occurs and ADP is released. Myosin head group adopts original conformation, sliding filaments past one another

110
Q

Describe how calcium triggers a change in tropomyosin and exposure of myosin binding sites

A

Muscle contraction is tied to calcium release from the sarcoplasmic reticulum – structure similar to smooth ER in skeletal muscle cells that stores of calcium Ca2+ ions

Nerve impulses signaling through the neuromuscular junction (NMJ) induce the release of calcium Ca2+ ions from the sarcoplasmic reticulum

Myosin binding sites on actin filaments are blocked by troponin/tropomyosin when calcium concentration is low

Calcium binding to troponin complex shifts troponin-tropomyosin complex, exposing myosin binding sites

111
Q

True or false:
Non muscle cells organize their actin and myosin filaments into sarcomeres.

A

False. Only muscles have sarcomeres.

112
Q

Describe why cytokinesis requires coordinated myosin contractility

A

Contractile ring composed of actin and myosin filaments

113
Q

Describe how non-muscle myosin is activated by calcium/calmodulin

A

Ca2+ binding to calmodulin induces a conformational change and allows calmodulin to bind to myosin light-chain regulatory kinase (MLCK)

MLCK/calmodulin complex then phosphorylates regulatory light chain of myosin II, activating the protein

114
Q

Describe other types of myosin paired to cargo or other intracellular components

A

Myosin I lacks a long tail and does not form dimers, instead the tail interacts with vesicles and other structures in the cell, which can be transported along actin filaments

Myosin V plays an important role transporting cargo towards the plus end of actin filaments, particularly in neurons

115
Q

What do cell cycle checkpoints do?

A

Detect (and repair) DNA damage.

DNA damage checkpoints prevent cells with incomplete/damaged genomes from replicating – prevents abnormal cell function and tumor development

116
Q

What are two primary mechanisms for DNA repair?

A
  1. direct reversal of the chemical reaction responsible for DNA damage
  2. removal of the damaged bases followed by their replacement with newly synthesized DNA
117
Q

What are ATR and ATM?

A

kinases that recognize single strand (ATR) or double strand (ATM) breaks in DNA. ATR and ATM activate Chk1 or Chk2, kinases that phosphorylate and inhibit Cdc25 phosphatases

118
Q

What does Cdc25 do?

A

removes inhibitory phosphorylations from Cdk1 and Cdk2, activating these kinases

119
Q

What stabilizes p53 and prevents its degradation?

A

phophorylation

120
Q

The p53 pathway is a major mediator of responses to stress and damage to the genome. Why.

A

P53 builds up and prevents the cell from progressing through a checkpoint. This is a method of cell cycle arrest.

Arrest gives the cell a chance to repair the double stranded break. If the cell cannot fix the break, higher levels of P53 will be generated and this typically leads to apoptosis.

A double stranded break leads to loss of a lot of genetic info.

121
Q

Give three examples of DNA damage

A

Deamination- loss of amine group. Becomes uracil. This messes up complementary base pairing. Leads to distortion in DNA through improper base pairing.

UV light and radiation. Energy from this light can cause adjacent thymine resides to crosslink and interfere with base pairing. Can cause issues with transcription.

Carcinogens cause cancer. Causes distortion in structure

122
Q

Describe how thymidine dimers can be reversed by photo reactivation

A

Energy from visible light used to reverse UV-induced dimerization of adjacent thymine residues

This repair mechanism is not present in mammals but is found in some other animals, as well as yeast and bacteria

123
Q

Describe base excision repair of cytosine deamination

A

Base excision repair is the removal of a single damaged base from a DNA strand

DNA contains U caused by a deamination of C.

Uracil removed by DNA glycosylase, sugar-phosphate backbone remains intact, but creates an AP site.

The gap is then rapired via DNA pol and ligation.

124
Q

Describe nucleotide excision of thymidine dimers

A

Damaged bases/bulky group additions induce distortion in DNA helical structure

Helicase separates DNA around lesion

Nucleotides surrounding lesion cleaved and removed by nucleases

Gap in molecule repaired by DNA polymerase and ligase

125
Q

Describe correcting mismatched bases during DNA replication

A

Methylation distinguishes parent strand from daughter strand, MutS binds to mismatched base followed by MutL

MutH cleaves unmethylated DNA at GATC sequence

MutS and MutL, along with helicase and exonuclease, cleave and remove DNA around mismatch

126
Q

Describe how DNA replication can continue through DNA damage lesions using special DNA polymerases

A

Polymerase stalls at DNA damage due to a thymidine dimer.

Specialized DNA polymerases are highly error prone and lack proofreading activity, but are recruited to synthesize across the lesion.

Normal replication then resumes, and the lesion i slater repaired via excision repair.

127
Q

Describe repair by non-homologous end joining (NHEJ)

A

These double stranded breaks can be repaired by simply rejoining the ends of the broken molecule, but this frequently leads to the loss of bases around the site of damage.

Small insertions and deletions (indels) are common with NHEJ

128
Q

Describe repair via homologous Recombination

A

Both strands of DNA at a double-strand break are digested by nucleases in the 5′ to 3′ direction. RecA binds to the overhanging 3′ ends, which then invade the other parental molecule by homologous base pairing.

The gaps are then filled by repair synthesis and sealed by ligation, yielding a crossed strand intermediate.

Cleavage and ligation of the crossed strands then yields recombinant molecules.

Undamaged homologous chromosome used as template to repair damaged chromosome

129
Q

What is apoptosis?

A

A form of “programmed cell death” that prevents molecules in the cell from being released onto neighboring cells

In contrast to necrosis – accidental death of cell resulting from acute injury

130
Q

What are apoptotic cells marked by?

A

exterior phosphatidylserine

131
Q

Describe how phosphatidylserine functions during apoptosis

A

Phosphatidylserine is found in the inner plasma membrane in normal, healthy cells

Apoptotic cells “flip” phosphatidylserine to the outer membrane, where it is recognized by phagocytic cells

132
Q

What are caspases?

A

promiscuous proteases that mediate apoptosis.

They cleave over 100 different cellular proteins.

133
Q

What is the general pathway of apoptosis regulated by?

A

Bcl-2 family member proteins regulate apoptosis through proapoptotic and antiapoptotic activity

134
Q

Describe the activation of caspases by Mitochondrial cytochrome C

A

Cytochrome c is usually found between the inner and outer membranes in mitochondria

Bax and Bak create pores in mitochondrial outer membrane, allowing cytochrome c to be released into cytosol, where they interact with Apaf-1 and Caspase-9 to form the apoptosome

Caspase 9 in apoptosome then cleaves and activates procaspase-3, leading to caspase-3 activation and apoptosis

Caspase 9 is a key initiator caspase in mammalian cells

135
Q

Describe P53 induced apoptosis following DNA damage

A

DNA damage leads to Chk2 activation and increased levels of p53

p53 induces transcription of pro-apoptotic target genes, whose expression leads to apoptosis

Level of p53 induction determine whether cell cycle arrest/repair or apoptosis will occur

136
Q

Describe how PI-3K /Akt suppress apoptosis and supports cell survival

A

Growth factor signaling through RTKs inhibits proapoptotic regulatory proteins like Bad and Bim

Akt also inhibits the proapoptotic FOXO transcription factors

137
Q

What are extracellular signaling pathways for apoptosis

A

TNF – Tumor necrosis factor

TNF induces TNF receptor trimerization and Caspase-8 recruitment and activation

Caspase-8 then cleaves and activates other caspases, while also cleaving and activating the proapoptotic regulatory protein Bid

Targets infected or cancer cells for apoptosis

138
Q

What oncogenes lie within the PI-3K/Akt pathway to block apoptosis

A

Proto-oncogenes found in the PI3K/Akt pathway include

Growth factors
Growth factor receptors
PI3K
Akt
Bcl-2

139
Q

What do early embryonic cell cycles don’t do?

A

incorporate G1 or G2 phases

140
Q

Describe variation during animal development

A
  • Early embryonic cell cycles don’t incorporate G1 or G2 phases
  • Rapid alternation of DNA synthesis and mitosis
    o It never grows, stays the same size as the oocyte
  • Surplus of cytosolic content
141
Q

What does Flow cytometry/ flow assisted cell sorter (FACS) do?

A

used to determine where cells are in the cell cycle based on DNA content

142
Q

Describe how Flow cytometry/ flow assisted cell sorter (FACS) works

A
  • Charge added to deflect cells into different test tubes based on fluorescent tag
  • ID cells based on characteristics stains/antibodies to see presence or absence
    o S has the most variable amount of DNA because cells split between 2n and 4n amount of DNA when replicating
    o More cells in G1 because it’s a bigger phase than G2
143
Q

What does passing the START regulatory point mean?

A

You committed to entering S phase and mitosis
o First identified in yeast cells

144
Q

Why would the cell cycle arrest during the START regulatory point?

A

o Low nutrient availability, mating signals, cells not being the minimum size

145
Q

If conditions are unfavorable for replication, what occurs?

A

cells exit cycle and enter G0 (quiescence)

146
Q

What is quiescence?

A

state of exiting cell cycle, however, Cells can reenter cell cycle in response to signals (growth factors)

147
Q

What is the restriction point?

A

like START regulatory point, but present in mammalian cells (START point in yeast cells)

  • Regulated by external growth factors in animals
    - START controlled by internal signals (cell size and nutrients)
  • Passing restriction point commits cell to S phase and cell cycle
  • Growth factors act on RTKS to activate MAPK and other growth pathways
148
Q

Why are checkpoints present in replication?

A

ensure genome fidelity before proceeding through cell cycle. Ensures damaged DNA is not replicated and passed on daughter cells

149
Q

What happens when you fail to pass a checkpoint?

A

cycle arrest and apoptosis

150
Q

How is cell cycle regulated?

A

cyclins and CDKs

151
Q

Describe Experiment 1 to discover CDKs: maturation promoting factor (MPF) first discovered during oocyte meiosis

A

-Progesterone treatment causes oocyte to progress from G2 to M phase
-Take cytoplasm from cell and inject in recipient oocyte in G2
o Cell progressed to M phase
o Shows there was some
cytoplasmic factor in donor
cell that drove recipient cell to
M phase
a. Discovery of maturation
promoting factor

152
Q

Describe Experiment 2 to discover CDKs: temperature sensitive mutants discovered that stopped cell cycle progression at START/restriction point

A
  • At high temperatures, cells arrested at START and stalled at G1
    o Mutant phenotypes induced at high temperatures
     Results from protein folding incorrectly at nonpermissive temperatures
153
Q

Describe Experiment 3 to discover CDKs: discovery of proteins during sea urchin development that underwent cyclical production and degradation

A

Cyclins build up in cell through interphase and degraded during mitosis
o Cyclins drive mitosis, but
drops when mitosis happens
-Some cyclins are proto-oncogenes
o Genes that drive cell
growth/mitosis that can also
promote tumor development
when mutated

154
Q

What is MPF?

A

Maturation promoting factor. A complex of Cyclin B and Cdk1

155
Q

Describe the Life cycle of Cdk1/Cyclin B: G2 to M transition

A
  1. Cdk1 inactive when not bound to cyclins
  2. Cyclin B synthesis upregulated in G2 to create MPF
    a. More cyclin B = more complex
    forms
  3. Cdk1 phosphorylated at Thr161 (activating), Tyr15 (inhibiting), and Thr14 (inhibiting)
    a. Adding phosphate activates all
    three, but complex not active
    because Tyr15 and Thr14
    inhibitory effects active
  4. Thr4 and Tyr15 dephosphorylated
    a. Removing phosphate = inactive
    Thr14 and Tyr15 = no
    inhibition = activated complex
    b. Another checkpoint
  5. End of mitosis with Cyclin B polyubiquitinated by anaphase promoting complex/cyclosome APC/C
    a. Cyclin B degraded to terminate
    MPF activity
156
Q

What are CDK inhibitors?

A

CDK inhibitors can function as tumor suppressors
o Inhibit cell proliferation and cell
growth
o Inhibitors mutated/
nonfunctional in cancer cells

157
Q

How does cell signaling feeds into cell cycle

A
  • Cyclin D rapidly degraded in G1 through APC/C polyubiquitination
    o No growth factors present,
    cyclin D levels fall
    o Cells don’t progress through
    G1 to S phase

1.Growth factors feed into Ras/Rak/MEK/ERK pathway to start cell cycle
2. Synthesis of D-type cyclins
3. Synthesis of Cyclin D is higher than degradation

158
Q

Describe Moving from G1 through S phase

A
  • P27 bind to inhibit Cdk2/Cyclin E complex activity
    o Increased cyclin E synthesis
    o P27 decrease through
    reductions in transcription
    and translation
    -Cdk2/Cyclin E not bound and phosphorylate P27
    o Phosphorylation = p27
    polyubiquitinated and
    degraded
  • Activated Cdk2/Cyclin E complex block APC/C activity to prevent cyclin degraded
    o Blocking APC/C activity
    increase cyclin D too, increasing
    cyclin D to increase cyclin E
    transcription?
159
Q

Describe how Cdk2/cyclin E is important for DNA replication

A

-MCM helicase binds to origins of replications/origin recognition complex (ORC) to form prereplication complex during G1

-Cdk2/Cyclin E and DDK phosphorylate MCM and proteins that associate with MCM to initiate DNA replication

160
Q

What does RNA Primase do?

A

Makes the short RNA primers for both Okazaki fragments and leading strands.

  • RNA primer binds, and DNA polymerase binds to 3’ OH RNA primer
  • Primer removed by RNAase H and 5’ to 3’ exonuclease
    o Gap in sugar-phosphate
    backbone joined by DNA
    ligase

-Both strands with continuous and discontinuous replication

161
Q

What does PCNA do?

A

helps DNA polymerase associate with DNA during replication

162
Q

Describe how PCNA helps DNA polymerase associate with DNA during replication

A
  • protein RFC loads PCNA onto the
    DNA
    o RFC released to load PCNA

-PCNA loads DNA polymerase onto template at primer-template junction

-Ring structure of PCNA holds DNA polymerase in place as it moves down template synthesizing new strand

163
Q

What do Single stranded binding proteins do?

A

stabilize exposed ssDNA

  • Single stranded DNA binding proteins bind to unwound strands of DNA
    o Stabilize molecule and protect
    from degradation
    o Prevent formation of
    secondary structures
164
Q

Certain DNA polymerases have proofreading properties to correct base mismatches. Describe this.

A
  • Polymerase excises mismatches nucleotide via 3’-5’ exonuclease
  • Synthesis proceeds with incorporation of correct base
165
Q

Telomerase replicates the ends of chromosomes. Describe this

A
  • DNA polymerases can’t replicate the 5’ ends of linear DNA molecules (telomeres)
  • Telomerase maintains ends of chromosomes through reverse transcriptase activity
    o Brings its own RNA template,
    which is complementary to
    telomere sequences
    a. Uses template to
    extend 3’ of one DNA
    strand
  • Primase and DNA polymerase then extend the complementary strand.
  • Telomerase active in germ and stem cells, but some somatic cells lack telomerase activity
    o Somatic cells telomeres
    shorten progressively with
    each round of cell division
    a. Cell aging shorten ends,
    and eventually shorten to
    important DNA
    b. Stop replicating after about
    50 replications
166
Q

True or false:
Replication origins spaced throughout genome

A

If only a single origin site existed in a mammalian genome, DNA replication would take 3 weeks

Cell Bio (3 decks)

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