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Health and Disease: Genes > Boyes V(D)J > Flashcards

Boyes V(D)J Flashcards

1
Q

Where does VDJ recombination occur?

A

Heavy chain in proB cells

Light chain in preB cells

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2
Q

What size is each domain of an antibody?

A

110residues

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3
Q

How many polypeptides is an antibody made up of?

A

4

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4
Q

How many types of light chain constant region are there?

A

2- lamda and kappa

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5
Q

How many types of antibodies are there?

A

5x10^13

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6
Q

Which cells can rearrange the DNA?

A

B cells

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7
Q

How many combinations of segments make up a heavy chain?

A

40V
25D
6J
=6000

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8
Q

How many kappa variable segments are there?

A

40

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9
Q

How many kappa Joining segments are there?

A

5

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10
Q

How many lamda variable segments are there?

A

30

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11
Q

How many lamda joining segments are there?

A

4

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12
Q

How many combinations can VDJ create?

A

1.9x10^6

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13
Q

Which proteins bind RSS?

A

RAG proteins

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14
Q

What are the 2 types of RSS?

A

23bp or 12bp

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15
Q

What is the sequence of 23bp RSS?

A

heptamer-spacer-nonamer

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16
Q

What is the RSS sequence of kappa?

A

V23- 12J

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17
Q

What is the RSS sequence of lamda?

A

V12-23J

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18
Q

What is the RSS sequence of heavy chain?

A

V23-12D12-23J

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19
Q

What is the sequence of the 12bp RSS?

A

nonamer-spacer-heptamer

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20
Q

Is the RSS spacer sequence conserved?

A

No

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21
Q

What is the structure of RAG1?

A

1040 residues,
C terminal active
DDE motif
binds nonamer

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22
Q

What is the structure of RAG2?

A

527 residues
N terminal active
C terminal PHD binds 11p chromosome
binds heptamer

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23
Q

Do RAGs have introns?

A

No

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24
Q

What is the method of VDJ recombination?

A

RAGs bind RSS making synaptic complex
RAG1 produces a single strand nick
RAG2 transesterification produces a dsDNA break
NHEJC excise fragment

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25
Q

What is the structure of the heavy chain?

A

V-D-J-intron-C1-intron-Hinge-intron-c2-intron-c3

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26
Q

How far apart can RSS be?

A

20kb- 1Mb

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27
Q

What does RSS in the same direction cause?

A

Inversion

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28
Q

How is junctional diversity added?

A 
Ku70:Ku80 binds ends
DNA-PK:Artemis opens ends assymetrically
P nucleotides added to fill in hairpin producing palindrome
TdT adds N nucleotides to heavy chain
exonuclease removed unpaired bases
DNA ligase 4 ligates ends
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29
Q

Where is junctional diversity produced?

A

Hypervariable region 3

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30
Q

When is junctional diversity produced?

A

light chain: pre-B cell stage

Heavy chain: pro0B stage

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31
Q

How much variation is produced by junctional diversity?

A

3x10^7

32
Q

Which constant chain do naive B cells express?

A

M or D immediately downstream

33
Q

How are antibodies targetted to membranes or for secretion?

A

25 C terminal residues

34
Q

Which antibody modifications are reversible?

A

Alternative splicing of IgM/D and membrane/secreted

35
Q

How is affinity of IgM and IgA raised?

A

J protein binds C chain to make pentamers or dimers

36
Q

What are the 5 isotypes of heavy chain?

A

M, D, E, A, G

37
Q

Which heavy chain cannot be produced by class switching?

A

M

38
Q

When does class switching occur?

A

In mature T cells that have been recruited to germinal centres in lymph nodes and recognising antigen.

39
Q

What are switch regions?

A

1-10kb long G rich upstream regions

40
Q

How does class switch recombination occur?

A 
AID binds transcribed ssDNA
Zn mediated C deamination
UNG removes U base
APE1 removes backbone to create a nick
Lots of nicks, some randomly align to create dsDNA breaks
NHEJC joins ends to remove fragment
41
Q

Can multiple class switches occur?

A

Yes but must be downstream each time

42
Q

What does somatic hypermutation do?

A

Fine tunes affinity through 3 hypervariable sites

43
Q

What are the 3 mechanisms of somatic hypermutation?

A

AID produces G=U mismatch

1) replication produces T in half daughter cells
2) UNG removes base, lesion bypass randomly inserts base
3) MMR elements insert A-T mutations

44
Q

Why does AID not produce dsDNA breaks in somatic hypermutation?

A

Lower concentration

45
Q

What are the 4 methods of adding diversity to the variable region?

A

V(D)J (1.9x10^6)
Junctional (3x10^7)
Combinatorial
Somatic Hypermutation

46
Q

What are the structural differences in T cell antibodies?

A

Only one receptor,
made of 2 chains alpha and beta
only one variable region

47
Q

How is diversity added to T cell antibodies?

A

No somatic hypermutation, more J segments

48
Q

What type of T cell antibodies are produced in the gut?

A

gamma and delta

49
Q

How are antibodies held in membranes?

A

complexes using 25residue C terminal motifs

50
Q

Where are antigens presented?

A

APC/dendritic cells with MHC2 for bacterial peptides or MHC1 for viral peptides

51
Q

How do T cells recognise antigens?

A 
MHC class 2 (+bacteria) recognised CD4 complexed antibodies on T helper cells
MHC class 1(+virus) recognised by CD8 complexes on cytotoxic T cells
52
Q

How is V(D)J regulated?

A

Limited to G1 phase by RAG2 pT490 degradation
RAGs only expressed in B and T cells
Epigenetics exclude RSS in one allele

53
Q

What phase is V(D)J recombination limited to?

A

G1

54
Q

How is V(D)J initiated?

A

Transcription removes H2A/B dimers to expose RSS in 35-40bp for ~6 minutes.

55
Q

What does transcription of antigen receptor loci cause?

A

H3K4me3 which binds RAG2 PHD

Acetylation opens chromatin structure and recruits remodelling complexes through bromodomains

56
Q

What are the characteristics of the enhancers of antigen receptor loci?

A

Tissue, stage and locus specific

57
Q

How has it been proved that transcription is essential for V(D)J?

A

Long sterile transcripts
Insertion of terminators downstream of J61 only allows transcription downstream of J49 promoter
Enhancer KO mice do not have V(D)J

58
Q

How does allelic exclusion occur in V(D)J?

A

Only one enhancer and only one allele in active centre of nucleus

59
Q

How has allelic exclusion been proved?

A

2 enhancers upregulates expression

60
Q

What type of disease does errors cause?

A

50% of all lymphiod cancers

61
Q

What is the main form of error during V(D)J?

A

Chromosome translocation during dsDNA breaks

62
Q

How can chromosome translocations occur?

A 
cryptic RSSs
End donation
RAG mediated transposition
ESC reintegration
Cut and run
63
Q

What size is the ESC?

A

20kb-1mb

64
Q

How many mutations does RAG mediated transposition cause?

A

1/44,000 recombination events

65
Q

Where has RAG mediated transposition occured?

A

THRalpha/HPT locus

IN VITRO

66
Q

What protects against RAG mediated transposition in vivo?

A

The C regulatory domain of RAG

67
Q

Where have cryptic RSSs been proved?

A

Sequencing of LM02 from chromosome 11 into T cell alpha locus of chromosome 14

68
Q

Where have cryptic RSSs been found?

A

LM02/alpha
SIL/SCL
TCR/IgH

69
Q

How do broken ends of chromosomes get incorporated?

A

RAG recognition of unusual hairpin structures

70
Q

What are examples of end donation?

A

BCL-2/IgH

BCL-1/IgH

71
Q

How common is integration of ESCs?

A

1/10,000 to 1/100,000 recombination events

72
Q

Where do ESCs reintegrate?

A

Cryptic RSSs upstream of an oncogene

73
Q

How do chromosome translocations cause cancer?

A

Bring oncogenes under control of strong promoter

74
Q

What unpublished data is there for ESCs causing cancer?

A

Cut and run of ESC with RSS bound to RAGs producing ssDNA cuts to produce free ends

75
Q

How has the link between chromosome translocation and Class switch recombination been proved?

A

AID KO mice can produce no Myc-IgH translocation even when stimulated with pristine and IL6 translocation stimulants

76
Q

What does AID overexpression cause?

A

Cancer

77
Q

How are chromosome translocations protected against?

A

Ku70:Ku80 complex hold cut ends for NHEJC to seal

Health and Disease: Genes (6 decks)

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