Apoptosis and Genome Stability

8/3/2019 Apoptosis and Genome Stability

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Apoptosis is a complex mechanism by whichcellundergo its own

destructionto control the process ofcell proliferationor it can bedue to in response ofDNA damage.


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Shrink

Develop bubble-like blebs on their surface

Have the chromatin(DNA and protein) in theirnucleus degraded

Have their mitochondria break down with the release

ofcytochrome c Break into small, membrane-wrapped, fragments

calledApoptic bodies

Release energy in the form ofATP andUTP.


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Programmed cell death is as needed for properdevelopmentTheformationofgap between thefingers andtoes of thefetus

requires the removal of tissue by apoptosis.


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Programmed cell death is needed to destroy cells thatrepresent a threat to the integrity of the organism. Cells infected with viruses

Cells with DNA damage

Cancer cells


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Intrinsic or mitochondrial pathway Extrinsic or death receptor pathway


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Someviruses associated withcancers use tricks to prevent apoptosis of

the cells they have transformed.

SeveralHuman papilloma viruses (HPV)have been implicated in

causing cervical cancer. One of them produces aprotein (E6) thatbinds andinactivates the apoptosis promoterp53.

Epstein-Barr Virus (EBV), the cause of mononucleosis and

associated with some lymphomaso produces a protein similar toBcl-2o which produces another protein that causes the cell to

increase its ownproductionofBcl-2. Both these actions make the

cell more resistant to apoptosis.


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Even cancer cells produced without the participation ofviruses may have tricks to avoid apoptosis.

Some B-cell leukemia's andlymphomas express high levels

ofBcl-2, thus blocking apoptotic signals they may receive.

Melanoma(the most dangerous type of skin cancer) cells

avoid apoptosis by inhibiting the expression of the gene

encodingApaf-1.


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Maintaining the stabilityof the genome is critical to cell

survival and normal cell growth. Thegenome can be stabilized at different levels from

different kinds ofmutations which causegenome damage.


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Telomere MaintenanceCell Cycle Check PointsRepairing the Mutations


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**Pif1p inhibits telomerase-mediated telomere elongation by directly removing telomerase from a DNA end.LIG4 is a human gene that encodes the protein DNA Ligase IV. Break-induced replication(BIR) is an efficienthomologous recombination.


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Common well characterized genome repair

mechanisms

Direct reversal of Genome damage

Excision repair

Mismatch repair Post replication repair

Recombination Repair


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Methyl group


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Repair Systems Type of Damage Repaired

MismatchReplication errors, including

mispaired bases and strands

spillage

DirectPyrimidine dimers; other specific

types of alterations

Base- excisionAbnormal bases, modified bases

and pyrimidine dimers

Nucleotide- excision

DNA damage that distorts thedouble helix, including abnormal

bases, modified bases and

pyrimidine dimers


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Genome-maintenance mechanisms are intimately linked to

apoptotic components, as indicates the high number of

proteins that interact withthe tumor-suppressor protein p53.

Interactions betweenapoptosis andgenome-maintenance

mechanisms include transactivation-independent and -

dependent functions, in which the tumor-suppressor protein

p53 works as amolecular node in the DNA-damage

response.

Also, severalcritical nodes that entangle apoptosis andgenome stabilityare cancer genes

Ex. ATM, BRCA1, BRCA2, MLH1,MSH2, MSH6 and TP53


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There are up to100 genes coordinately working inapoptosis pathways


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SeveralDNA repair proteins can stimulate apoptosis in

response to DNA lesions. Comparative Genomics data are available about the

evolutionary scenario that functionally links apoptosis to

genome stability gene network. There are around180 genes participating inhuman apoptosis

andgenome-stability functions


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The histogram shows the distribution of 180 human orthologs according to the roots inferred in

the eukaryote species tree. Inset graph shows the presence fraction of orthologs of eachSpecies

Tree Nodes (STNs). Diverse important events related to the roots of sets of genes are pointed

along the STNs. Chromosome stability (CS).


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Apoptosis is a multi-step, multi-pathway cell-death programmethat is inherent in every cell of the body. Incancer, the apoptosis

cell-division ratio is altered. Cancer treatmentbychemotherapy

and irradiationkills target cells primarily by inducing apoptosis.


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The recent discoveries have added a new dimension to our

understanding of thegenome stability mechanisms, shed lighton differentgene networking pathways, and stimulated the

development of potential new therapies. I hope we will share our

hands in this research to make miracles.


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Cooper,G.M., Hausman,R.E., (2009). Programmed call death. In. The cellA molecular approach. (5thEd), ASM press, Newyork, 693 705.

Kindt, T.J., Goldby, R.A., and Osborne, B. A., (2007). Programmed celldeath is an essential homeostatic mechanism. In. Immunology. (6thEd),

W.H. Freeman and company, Newyork, 26-28.

R.D. Kolodner,* C.D. Putnam, K.Myung.,(2002). Maintenance of GenomeStability inSaccharomyces cerevisiae. In. Science Magazine.Vol.297.,552-

557. Mauro A. A. Castro Et.al.,(2008). Evolutionary origins of human apoptosis

and genome-stability gene networks . In. Nucleic Acids Research, Vol. 36,No. 19,62696283.


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Jan H. J. Hoeijmakers.,(2001)., Genome maintenance mechanisms forpreventing cancer. In. NATURE.,VOL 411.,366-374.

J.B.Boule and V. A. Zakian.,(2006)., Roles of Pif1-like helicases in themaintenance of genomic stability. In. Nucleic Acids Research, 2006, Vol. 34,

No. 15 41474153. Greider CW, Blackburn EH.,(1985).,Identification of a specific telomere

terminal transferase activity inTetrahymena extracts. Cell; 43:405-13.

Greider CW, Blackburn EH.,(1989) A telomeric sequence in the RNA ofTetrahymena telomerase required for telomere repeatsynthesis. Nature;

337:331-7.


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Presented by,D evarapalli P ratap

N Y

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Apoptosis and Genome Stability