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All The Stuff Flashcards

1
Q

What affects gene expression

A

PTM
Chromatin remodellers
Epigenetics (TF)

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2
Q

What is a chromatin remodeller

A

It is a protein that can move the nucleosome out of the way for the transcription machinery to access the gene. It requires ATP
It can also work chromatin
But if works with TF to establish and maintain gene expression states

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3
Q

Cell memory is achieved by

A

Using epigenetics markers such as Histone acetylation and DNA methylation

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4
Q

What are PcGs

A

Polycomb group - epigenetic regulator that mark a gene off
Help maintain gene expression. It’s highly conserved
Help maintain SC fate in eukaryotes

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5
Q

Establishment of gene pattern during embryonic development is via

A

Maternal deposition of mRNA
Pair rule
Segment polarity - off genes tag with PcG and on with TrxG

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6
Q

Maintaining gene pattern is via

A

Transmission of pattern after disappearance of early factors

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7
Q

Maintaining LT gene expression

Gene expression needs to be carefully regulated and maintained during diffentiation esp during what stage of development

A

Embryonic

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8
Q

What genes must be on all the time to maintain pluripotency

A

OCT4 SOX2 Nanog

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9
Q

What is the gene expressed in the trophectoderm after ICM is formed

A

CDX2

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10
Q

Assays for NHEJ

A
  • FACS to observe localisation of NHEJ proteins (ku, H2Ax, DNA pkcs
  • Use direct assay (I-Scel)
  • culture cells that have proteins expressing GFP in Brdu for real time observation
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11
Q

Factors that result in human diseases

A

Environmental factors
Lifestyle
Genetics
Epigentics and imprinting

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12
Q

What are inherited diseases

A

Inherited diseases are essential,y the inheritance of trait quite often determined by one or multiple genes (latter more common). I.e. They can be multi genic or monogenic

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13
Q

Monogenic diseases are more rare. Why is that

A

It is rare because mutation often cause deleterious consequences and therefore are more susceptible to selective pressure

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14
Q

Examples of monogenic diseases related to DDR proteins

A 
Seckel syndrome - ATR/ATRIP 
FA- FANC genes 
AT - ATM, chk2
Bloom- BLM (helicase 
Werner - WRN
Li fraumani - p53, chk2
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15
Q

Naked virus DNA

A

Papilloma parvo adeno

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16
Q

HPV genome and cancer type

A

Small Double stranded DNA circular and oripharygeal/ cervical

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17
Q

Infection route of HPV

A
  1. Enter through abrasions in epidermis
  2. Infect basal cells and become quiescent (low viral expression
  3. Begin expressing protein as basal cell differentiate into other cells
  4. Expression of early proteins E7/6 makes cells enter cell cycle thereby promoting cell division and inhibiting apoptosis and inhibit host cell defence
  5. Expression of late structural proteins
  6. Assembly near cell surface and disseminate
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18
Q

Function of E6 and E7

A

E7 will bind to hypophosohrykated pRB and result in release of E2F1 which promotes cell progression. However this will activate host cells defense response and so E6 will come in and inhibit host cel defense by tagging p53 for degradation via E3A6

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19
Q

What other proteins can E6 inhibit

A

P53
MGMT (DNA transferase
P300 (HAT)
SSBR via decreasing ATM

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20
Q

Adenovirus characteristics

A

Small dsDNA genome that is linear
Cause mild respiratory diseases
Good carcinogenesis model

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21
Q

What does E1/2 protein do in host cell

A

Form replication centre and activate DDR response

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22
Q

E1 and E7 can activate DDR checkpoints independent of each other (t/f

A

T

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23
Q

Why does wild type adenovirus inhibit DDR

A

Because DNA virus replicate in the nucleus and that the viral genome can be recognised as the host cells own DSB. If the viral DNA is repaired by the DNA repair machinery, it will become too big for capsid packaging

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24
Q

Why does virus activate DDR?

A

We don’t quite know but…

  1. Virus presence activate stress response which trigger DDR
  2. A standard antivirus mechanism in immunity
  3. Host cell recog viral DNA as own DSB
  4. Virus deliberately activate mechanism which may or may not help viral replication
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25
Q

mTOR1 and mTOR2 complex difference

A

1) contribute to cell growth via RhebGTPase (raptor protein and sensitive to rapamycin - promote growth via promoting ribosomal production and protein synthesis and inhibiting degradation of proteins
2) contains rictor protein and is insensitive to rapamycin - helps activate Akt

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26
Q

Rictor and raptor containing protein are …

A

MTOR2/1

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27
Q

ICL Can be induced by

A

Endogenous reactive intermediates (acetaldehyde, formaldehyde)

  • acetyalhyde intermediate of alcohol metabolism (alcohol dehydrogenase - DNA DNA crosslinks
  • formaldehyde (histone and DNA demethylation intermediate; ADH5) - protein crosslinks

Exogenous - Drugs like cisplatin, alkylating agents

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28
Q

FA ICL repair can inhibit what pathway

A

NHEJ

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29
Q

Defect in FANC repair pathway is backup by which pathway

A

NHEJ but can cause toxic ending

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30
Q

How does ICL Pathaay work

A

ICL sensed when replication fork come across it during replication
Dissociation of CMG of the MCM complex will recruit FANCD2.I complex
Formation of core complex (fancACELG)
The FANCD2 complex is UBI by core complex and the UBI will be recognised by UBI binding nucleades which unhook DNA
Recruitment of specialised polymerase (REV1, ZETA) will resynthesis DNA by bypassing bulky lesions (thy have less restrictive active site to accommodate lesion). ICL is clipped and filled in

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31
Q

Strategies for anti angiogenic factors

A
  1. Block VEGF receptor - herceptin (trastuzumab)
  2. Block RTK (prevent autopi) - sunitinib (sutent)
  3. Soluble receptor - aflibercept
  4. Neutralising antibody - avastin/bevacizumab
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32
Q

Problem arise in what stages of the cell cycle for ICL lesion to be sensed

A

S phase when replication fork encounter lesion

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33
Q

If cell force to pull ICL apart will cause what type of consequences to the newly formed chromosomes

A

Anaphase bridge snap - forms micro nuclei and radial chromosome in FA
Can cause mitosis catastrophe where cells undergo NON-p53 mediated apoptosis

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34
Q

How does drinking and smoking cause foetal abnomalities

A

Formation of acetaldehyde and formaldehyde endogenously during alcohol and histone degradation can impair FA-ICL repair pathway and protein-DNA cross links resulting in cell death

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35
Q

Mechanism of SSBR

A

PARP bind to DNA ends
XRCC1/DNA Lig3 recruited
PNK Resection and pol b synthesis
Relocation by lig3

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36
Q

Tumour cell secretions and function

A

Proinflammatory cytokines - CSF1 recruit MP
Immunosuppressants
Tumour derived stimulating factor (cell priming)
S1P homing of lymphocyte and LPa to promote lymphocyte entry

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37
Q

Antitumour MP function

A 
Antitumour 
Cytotoxic 
Recruited during acute inflammation 
Kills tumour cells secrete proinflammatory cytokines (TNFa) 
Produce ROS
Participate in Th1 immunity
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38
Q

M2 MP function

A

Pro-tumour development and found in most tumours
Secrets immunosuppressive cytokine IL10
Promote growth and tissue remodelling and also angiogenesis
Comes in during chronic inflammatory phase

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39
Q

What is DDR1 and function

A

Oncogenes TK that binds to collagen

Ligand is collagen and it will autophosphorylate to drive survival and growth

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40
Q

Concept of coevolution of stroma with cancer

A

Stromatogenesis
Evolving of stroma due to tumour influences - stroma is primed by tumour cells which will facilitate stroma growth towards tumour cells liking

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41
Q

Principle of Analysing diseased human genes

A

1) find sequence that are close together as they as likely to be inherited together using genetic markers
2) the mutation shared by affected individuals through common descent will be surrounded by shared alleles at nearby loci

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42
Q

Means of tracking linkage using genetic markers

A

1) restriction enezyme markers - mutation can affect how the enzymes cut - less accurate
2) SNPs - single nucleotide polymorphism marker - illumina colours DNA bound to the probe and can compare to GWAS
3) genome sequencing of particular regions or target gene fragment

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43
Q

ZFN example

A

FOKI

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44
Q

What does FOKl recognise

A

Triplets

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45
Q

What does TALEN a stand for

A

Transcription activator like effector nucleases

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46
Q

What does TALEN target

A

One single nucleotide - more specific

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47
Q

RGEN Is what and an example of this is

A

RNA guided engineered nuclease

CRISPR Cas9

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48
Q

The walburg effect

A

Cancer cells has altered metabolism and can increase lactate production in the presence of O2 to generate NADH

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49
Q

What are the two things that cancer cells love for energy production

A

Glucose and glutamate (support cell growth)

*ALL -L-arginine

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50
Q

Why use glycolysis in cancer cells?

A

Irreversible damage to mitochondria energy production due to TCA cycle block (succinate dehydrogenase mutation and Malate enzyme mutation) - walburg effect to fuel glycolysis further

Changes to enzyme expression due to altered signals -cMyc PTEM HIF1

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51
Q

Tumour cells consumes so much energ that patient show what typical symptom

A

Cachexia (muscle wasting) - body goes into starvation mode

52
Q

What is E1B55K

A

Part of E3 that can tag p53 for degration after complex binding to either E4/6

53
Q

Effect of phosphorylation on histones

A

Position is important - alters H1 stability binding to nucleosome
Very high during mitosis
Condensation of chromatin - H3K9/27me + H3S10 or S28P
Opening of chromatin - H3K9/27 ace. + H3S10P
(On lysine residue)

54
Q

What does TDT stand for and what does it do

A

Terminal deoxynucleotidyl transferase

Add 1-3 nucleotides at junctional sites during VDJ recombination before NHEJ relegation to increase receptor diversity

55
Q

MLL complex has what activity

A

It’s a TrxG that has H3K4 methyltransferase activity which counteracts PcG activity

56
Q

Death Luganda include

A

FAS ligand on T cells

TNF receptor

57
Q

Purpose of apoptosis

A

Regulate cell no.
Morphogenetic during embryonic development
Prevent abnormal cell proliferation thereby preventing cancer
Rid old cell to prevent accumulation of mutational events

58
Q

CtlP binds to MRN to promote HR

A

T

59
Q

ATR/ATRIP activation in response to DNA lesions that impede DNA replication. Is it directly activated by DSBs?

A

No, it is indirectly activated by DSB. RPA will bind to the damage DNA which recruits ATR/ATRIP. Hence ATR is activated after ATM to sustain checkpoint activation

60
Q

RNF168 mutation results in what syndrome

A

RIDDLE

61
Q

Ca dependent and independent binding of cell cell adhesion

A

Dependent - E-cad

Independent - nectin

62
Q

Oestrogen activated cells indirectly via

A

Transcription of proteins that produce autocrine activity to stimulate cell growth

63
Q

Product of oestrogen transcription

A

IGF1 TGFa Progesterone

64
Q

TAF1/2 are called

A

1- constitutive transcriptional activating function

2- ligand inductively transcription activating function

65
Q

Often mutation in oncogenes are what type of mutation (gain or loss)

A

Gain of mutation with hotspots

66
Q

Mutation of RAS often occurs on where

A

Missense on G12/13 Q61 which decreases GAP sensitivity (take off Pi)

67
Q

What are protooncogenes

A

Cellular regulatory genes that positively regulate the cells whereby mutation of which can drive cancer (cell growth)

68
Q

Gabetespid can inhibit hsp90 to inhibit what

A

To inhibit cell proliferation by destabilising p53

69
Q

P14 function

A

Inhibit CDK4 and MDM2

70
Q

P53 is what type of protein

A

Tetramer that can bind to DNA and drive transcription. Also a TSG that trigger cell cycle arrest and apoptosis in response to cellular stress

71
Q

Neuro blastoma has amplification of what gene

A

CMYC (MYCN esp)

72
Q

Resistance of tumour cells against alkylating agents

A

Normally combination

1) decrease entry or increase exit of agent
2) inactivation of agent in cell by expressing enzymes
3) increase DNA repair to overcome lesions produced by agent

73
Q

Tumour cell produce LPA which does what

A

1) promote lymphocyte Homing - promote T/B cell entry to tumour cell resulting in depletion of lymphocyte in blood. Patient susceptible to infections
2) promote angiogenesis
3) promote tumour growth and formation
4) produce neuropathic pain

74
Q

Function of S1P

A

Secreted by tumour cell to help retention of lymphocytes which results in lymphocytopenia

75
Q

CAF produce what

A

Dense collagen matrix making ECM desmoplastic and hard for drug diffusion. Secrete MMP2 which promote tumour invasion by ECM breakdown

76
Q

Hodgkin cells produce what to evade immune elimination

A

PDL1 - binds to T cell to prevent activation (Tc)

77
Q

How does salt contribute to gastric cancer

A

High salt levels can directly damage gut wall which increase exposure to carcinogens. H. Pylori is also shown to be associated with salt-induced gastric cancer

78
Q

Haem and gastric cancer

A

Haem can catalyse ROS formation which can result in the initiation of oxidative chain reaction (e.g. Lipid peroxidation).
Free haem is abundant in red meat and can also drive ENOS (endogenous nitrosocompound, carcinogen) formation

79
Q

H pylori cause mainly what type of gastric cancer

A

Distal (non cardia) gastric cancer

80
Q

Therapeutic options for p53

A

1) restore WT p53 activity by giving ARP246 - restore folding of mutant protein and sensitise them to cisplatin and doxorubicin
2) deplete p53 mutant by giving Ganetespid which binds to HSP90 (normally it stabilise p53 mutant) so now p53 is degraded due to MDM2 activity

81
Q

INK4 esp p16/14

A

P16 inhibits CDK4/6

P14 inhibits CDK4, MDM2 but mutation melanoma

82
Q

Common mutation in RAS

A

98% hotspot in G12/13 Q61

83
Q

Mutation in what oncogene result in glionlastoma

A

NRAS

84
Q

Mutation in G12/13 and Q61 decrease sensitivity if what protein

A

GAP(takes Pi off)

85
Q

Mutation in what causes neuroblastoma

A

MYCN (amplification

86
Q

Hallmarks of cancer - ‘SEE AIR’ and what the term mean

A

Depicts means in which cancer use to survive and grow

Sustain proliferation signalling 
Evade immune system 
Enable replicative immortalisation 
Angiogenesis 
Invade and metastasis 
Resist cell death
87
Q

Imatinib (gleevec) MoA

A

Targets ATP binding site of ABL tyrosine kinase (competitive binding)

88
Q

Avastin MoA

A

A neutralising Ab that binds to VEGF2 receptor

89
Q

Herceptin MoA

A

Binds to EGFR to prevent downstream signalling

90
Q

Imatinib binds to ATp binding site of ABL cytosolic TK to prevent

A

Phosphorylation of tyrosine residue of the substrate thereby preventing downstream signalling

91
Q

95% haematological response for 18 months using imatinib

A

True

92
Q

T315I is what type of mutation in what disease

A

Acquired substitution mutation of threorinine to isoleucine at position 315. Which is the ABL TK substrate binding domain. Mutation overcome by ponatinib that is less specific and can accommodate binding site change in CML refractory Patients

93
Q

Resistance to imatinib mechanism

A

1) change drug binding affinity

2) alteration in binding site (conformation stability)

94
Q

ARF246 does what to p53

A

Restore correct folding of mutant p53

Increase sensitivity of chemo resistant cells to cisplatin and doxorubicin

95
Q

The more hypoxic the tumour

A

The more likely it drives invasive and metastatic development

96
Q

CDK activation requires

A

Binding of cyclin and subsequent dephosphorylation of the inhibitory phosphate

97
Q

Metastasis is

A

A tumour deposit that is derived from but discontinued with the primary tumour

98
Q

Anoikis def.

A

Apoptosis due to inadequate adherence of the tumour cells to the substratum

99
Q

MTOR1 activates what TK achieve cell survival

A

Sk61 kinase

100
Q

DIABLO complex does what

A

Aka SMAC. Released from MP and binds to IAF (inhibitory apoptotic factors) which prevent Caspase activation thereby preventing apoptosis

101
Q

T(8;14)

A

Burkit

102
Q

T(14;18)

A

Follicular lymphoma

103
Q

T (15;17)

A

APML - Faggot cell present give ATRA/RA to allow differentiation

104
Q

Fulvulserant

A

SERM that is a pure oestrogen antagonist

Degrade ER

105
Q

SNail and Clip and SLUG upregualtion causes

A

Down reg of Ecad

106
Q

PDGF and Ang1 MoA

A

Stabilises pericyte at last stage of angiogenesis

Ang1 also activate AKT which inhibits vessel modelling (antagonised by ang2

107
Q

Ang2 and Ang1 function

A

Ang2 inhibits pi3k pathways and promote angiogenesis

Ang1 promotes pi3k and thus promote anti-inflammation /antiapoptosis/ antipermeability

108
Q

Rapamycin MoA and what it is use for

A

It is an immunosuppressant that is used to prevent organ transplant rejection
Works by inhibiting mTOR1(raptor containing protein) thereby preventing T/B activation by decreasing sensitivity to IL2

109
Q

Beta catenin is tethered to E-cad, why is this important in EMT

A

Beta catenin is normally degraded via GSK3/APC/axin complex and loss of E-CAD or dissociation of Beta catenin is then allowed to translocate into nucleus and bind to TCF family to activate transcription

110
Q

Structure of inositol phosphate

A

Inositol head
A phosphate attached to it
Glycerol backbone
2FA chain

111
Q

What does SOS do

A

SOS is a GEF that adds GTP onto RAS

112
Q

Is EMT reversible

A

Yes

113
Q

Invasion of tumour cell needs

A

Invasion requires expression of proteolytic enzymes e.g. MMPs which breaks down ECM and invadopodia which are actin protrusion that act with the enzymes to degrade basement membrane and dense stroma

114
Q

What is anoikis and its role in metastasis

A

Apoptosis due to inadequate adherence to substratum

Cancer can detach from primary tumour mass to overcome this and prevent death

115
Q

Cancer hijacks chronic inflammatory response via TF and use EMT to migrate. What TF especially does it use

A

SLUG, stimulated by TGFb and RTK activation

116
Q

E selectin interact with what molecule to promote adherence

A

Integrin

117
Q

Rare limiting step of metastasis is

A

Colonisation at secondary site

118
Q

Models for non random metastasis are

A

1) anatomical model - route in which tumour cell travels determine metastatic site
2) seed and soil model - cancer cell express receptors that target site which can produce GF (or favourable destination - predetermined premetastatic niche

119
Q

What does cancer do to avoid immmune activation

A

1) downregulate MHCI
2) express death ligand to inactivate T cells (FASL, PDL1, CTLA4)
3) immunosuppressive cytokine secretion (IL10) and stimulate proinflammatory cytokine production (TNFa)
4) recruit Treg

120
Q

How does P53 regulate MDM2

A

After p53 action fulfilled, P53 will bind between exon 1 and 2 of the MDM2 gene and result in transcription of MDM2 (autoregulatory loop)

121
Q

Mutation of p53 mostly occur in

A

Arg228 missense

122
Q

Atm autophos at where

A

Ser1981

123
Q

Telomere repetitive sequence

A

10-15kb with many TTAGGG repeats

124
Q

Tumour cell hijack chronic inflammatory response via

A

SLUG transcription factor activated by TGFb and RTK activation

125
Q

Gefitinib MoA

A

Inhibit EGFR TKD preventing auto Pi of receptor

Used in NSCLC

126
Q

SRC phosphorylase PTEN to inhibit PTEN

A

T

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