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V(D)J Recombinaton
V=variable region
J=joining region
- A: starts in the germ line
- B: B cell DNA transcribed into Transcribed RNA then RNA splicing splices into Spliced mRNA which is then translated into a light chain protein
- C: heavy chain protein
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Recombinaton "signal sequences"
- 2 types of signal secuences
- one has a 12bp spacer (surrounded by a 7mer and a 9mer)
- second has a 23bp spacer (surrounded by a 7mer and a 9mer)
- A: recombination signal sequences
- B: single strand cleavage
- C: herapin formation
- D: herapin opening fusion conde of segments-->further recombination
- D2: single joint formation-->DNA non homologous end joining proteins--> discarded
rag1 and rag 2 bind to the signal sequences to for a hair pin loop
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DNA damage and repair
- extrinsic damage: ultraviolet radiation, drugs, (ROS), (IR)
- intrinsic damage: VDJ recombination, Class switching recombination (CSR), Somatic hyper mutation (SHM)
- Other damage: telomere shortening, aging
- Sensing: variety of sensing proteins
- Signal transduction:
- Outcome: Senesence(P53), Apoptosis(P53), transcriptional response, cell cycle arrest, DNA repair
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DNA Damage in the immune system
- Bone Marrow:
- Blymphocyte development: VDJ recombination, proliferation, ROS, telomere shortening
- Hemapoptoetic stem cells: selfrenewal, proliferation, ROS, telomere shortening
- Thymus:
- T lymphocyte developement: VDJ recombination proliferation, ROS, telomere shortening
- Secondary Lymphoid Organs:
- B lymphocytes:CSR, SHM, Clonal expansion, ROS, Telomere shortening
- T lymphocytes: endegenous proliferation and clonal expansion, ROS, telomere shortening
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Component defects in V(D)J recombinaton
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Non Homologous End Joining (NHEJ)
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Mutatons affectng the immune system and DNA repair
- hypomorphic: loss of most function but retains some residual function (like a null allele)
- types of mutations:
- Artemis
- DNA-Lig 4
- Cemunnos
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Good damaged goods
- Deamination: activation induced deamination, switches thymine to uracil
- damaging the dna can also lead to improperly placed bps which contribute to dna diversity
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Base"excision"pathway
in the CSR pathway: activation induced deaminase
Generatng mutatons to enhance diversity in the immune system
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Generatng mutatons to enhance diversity in the immune system
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Translesion"DNA"synthesis"
translesion proteins and enzymes have less accuracy in putting bps thus contributing to dna diversity
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