Cell Death Flashcards
All cells can take apart in this form of cell death. Inflammation occurs and it is characterized by cell membranes swelling and rupturing, the cytoplasm increased vacuolation, organelles degrade, and mitochondria swell. The nucleus clumps and randomly degrades DNA. Two key players are involved, RIP1 and PARP1 which target the mitochondria. What kind of cell death is this and what are the mechanisms?
Necrosis
Calcium overload, mitochondrial uncoupling, increased oxygen consumption excessive ROS ATP depletion are the mechanisms of necrosis. Caspases are not involved.
Hematopoietic cells and their liquid tumor counterparts can take place in this kind of cell death. Inflammation does NOT occur. It is characterized by cell membrane blebbing and fragmenting into apoptotic bodies. The cytoplasm shrinks and fragments and in the nucleus chromatin condenses and degrades leading to nuclear fragmentation. What kind of cell death is this and what are the mechanisms?
Apoptosis
Cell membrane loses its aasymmetery and phosphatidylserine becomes exposed, it is caspase and mitochondria dependent.
Triggered by DNA damage death receptor signaling and cell membranes via activation of sphingomlyelinase to create ceramide. Also damage to the mitochondria.
What are the sensors, mediators and effectors in apoptosis?
Sensors are ATM, literal receptors, and the mitochondria.
Mediators are p53, anti apoptotic BCL2 family and pro apoptotic BH3 famikly and BAX. Cytochorme C and apoptotic protease activating factor 1
Effectors are caspases. Initiators are caspase 8,9,10 and executioners are 3,6,7
This type of cell death is responsible for degrading long lived proteins and organelles to generate macromolecules and ATP. It can occur in all cells and inflammation does NOT occur. It is caspase independent and increases lysosomal activity. It is characterized by membrane blebbing, accumulation of two membrane autophagic vacuoles and the nucleus undergoes partial chromatin condensation and no DNA fragmentation occurs. What is this and what are the important players?
Autophagy, includes Atg, Beclin 1, and Microtubule associated protein 1A and 1B.
Beclin and Atg6 initiate the formation of autophagosome
What is the mechanism behind autophagy?
Beclin forms the initiation complex and is released from Bcl-2. Two different conjugation cascades LC3-II and Atg5-12 elongate the nucleation complex. The limiting membrane sequesters cytosolic cargo and seals itself to form an autophagosome
This type of cell death is caused by aberrant mitosis and in mammals is mainly associated with deficiencies in the cell cycle checkpoints. What is it?
Mitotic catastrophe.
Characterized by no change in the cell membrane but the cytoplasm gets larger and forms a giant cell. The nucleus is characterized by micronucleation and multinucleation and fragmentation. Premature chromosome condensation and formation of nuclear envelops around the cluster of chromosomes.
What cells are involved in mitotic catastrophe and what is the mechanism of induction?
Most dividing cells can have this happen. No inflammation occurs and it is caspase independent at the early stage and occurs due to abnormal CDK cyclin B activation.
Mechanism is defects in cell cycle checkpoints such as p53 in the G2 checkpoint, BUBR in the spindle checkpoint and increase expression of multiple mitotic checkpoint genes such as APC in spindle assembly.
Also hyperamplification of centrosomes in CDK2/cyclin E/A S phase
Also caspase 2 activation during metaphase which delays apoptosis
What is the fate of cells that undergo mitotic catastrophe or have aberrant mitosis?
They die without exiting mitosis (mitotic death), they can also proceed to G1 and continue division for many cycles and undergo death eventually (delayed cell death), or they can exit mitosis and undergo permanent G1 arrest called senescence
Under a microscope you see a cell that has a normal membrane but a cytoplasm with increased granularity and flattening. The nucleus has a distinct heterochromatic structure as well. What is going on?
Senescence, permanent cell cycle arrest.
All types of cells can undergo this and inflammation occurs but it is due to secretory factors from the cell itself. The same DNA damage responses that activate the cell cycle checkpoints can lead to this.
There are two pathways:
P53-P21 and P16-RB pathway
BER?
Single base mismatches and NON distortions such as depurination or deaminations.
Detected and removed by DNA glycosylases and AP endonuclease cuts the phosphodiester bond
NER? What disorder is associated with impaired NER?
Fixes distortions in the DNA such as thymine dimers caused by UV, or chemical adducts.
Associated with XP, an autosomal recessive disease with mutations in the nucleotide repair enzymes, hypersensitivity to sunlight prone to skin cancers.
TCR? Associated disorder?
Repairs damage by having the RNA polymerase stall at the lesion, and then two proteins called ERCC6 and ERCC8 come in and recognize the stalled polymerase and recruit more repair proteins.
Cockayne syndrome an autosomal recessive disorder with mutations in the ERCC proteins. Results in progeria, photosensitivity, hearing and eye abnormalities.
MER and associated disorder?
Repairs damage from DNA replication due to a mismatched nucleotide getting inserted into newly synthesized strand.
Hereditary nonpolylposis colorectral cancers, lynch syndrome. Mutations in one of the alleles coding for MER complex results in unrepaired DNA damage leading to cancer.
NHEJ?
Doesn’t need a template, “clean up and stitch”. Can result in translocations and neoplastic chromosomal rearrangements
HR?
Requires a template strand to fix the break. Occurs after replication but before division.
