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MOBILE ELEMENTS ARE USED AS TOOLS! MOBILE ELEMENTS ACT AS GENETIC MARKERS IN EVOLUTION STUDIES MOBILE ELEMENTS ARE USED IN FORENSICS ERVs HAVE BEEN USED TO STUDY INFECTIOUS DISEASE AND EMERGING VIRUSES RETROVIRUSES AND DNA TRANSPOSONS ARE USED FOR GENE THERAPY . . . EVEN TO TREAT CANCER Retroviruses are used for Gene Therapy LTR gag pol env LTR Packaging Signal = Vector GENE X LTR Gag Pol Env Packaging Cells 10 KB in size LTR Non-replication competent virus containing gene X, pseudotyped with selected envelope Gene Transfer GENE THERAPY SUCCESSES AND FAILURES SCID is often called "bubble boy disease". SCID became widely known during the 1970's and 80's, when the world learned of David Vetter, a boy with X-linked SCID, who lived for 12 years in a plastic, germ-free bubble. He died after a bone marrow transplant. A recessive disorder of a mutation in the adenosine deaminase (ADA) gene causes SCID. Gene therapy successfully replaced this gene in several ADA patients. Researchers have also successfully used gene therapy to cure hemophilia in mice and dogs Plasmid containing VEGF-2 has been delivered to damaged heart tissue via catheters. VEGF-2 promotes the growth of new blood vessels that are required to provide oxygen-carrying blood to heart muscles to compensate for the blocked heart arteries. Gene therapy has been successfully used to replace p53 in tumor cells or target tumor cells because they lack p53 (Adenovirus used in the later case) SOME FAILURES: In September 1999, 18-year-old Jesse Gelsinger died after being treated for a rare liver disease using a gene carried by a viral gene vector, which was directly blamed for his death. A few patients who were cured of SCID caused by a mutation in the IL2RG gene developed leukemia. CELL CYCLE Mitotic Phase M G2 G1 S Interphase Prometaphase Metaphase Anaphase Prophase Gap2 cell growth transcription translation production of proteins for mitosis Telophase Cytokinesis M G2 G1 S DNA Synthesis Gap1 cell growth transcription translation organelle synthesis INCOMING SIGNAL (Growth Factors) Cyclin B CDK 1 Cyclin D CDK4 M G2 G1 S Cyclin A CDK2 Cyclin E CDK2 DNA is damaged Cell size is too small for cell division Sister chromatids do not separate M G2 G1 S DNA is not completely synthesized Cell enters cell cycle when it should not The cell does not produce enough of the organelles or products needed for DNA synthesis and cell division DNA is damaged but DNA synthesis proceeds CELL CYCLE CHECKPOINTS Critical points in the cell cycle that are tightly regulated. Checkpoint failures lead to unregulated cell division or cancer. M G2 G1 S Metaphase Checkpoint chromosome attachment to mitotic spindles G2 Checkpoint cell size chromosome replication DNA damage M G2 G1 S G1 Checkpoint Checkpoint failures lead to unregulated cell division or cancer. cell size nutrient levels DNA damage DNA DAMAGE Apoptosis Cyclin D M P53 Continue CDK4 G2 G1 RB E2F S E2F RB G1 Checkpoint cell size nutrient levels DNA damage E2F cyclin E Cyclin E CDK2 P53 and RB are TUMOR SUPPRESSORS Incomplete chromosome replication Cyclin B G2 Checkpoint CDK 1 Cyclin B cell size chromosome replication DNA damage CDK 1 M DNA DAMAGE G2 G1 P53 S CDK1 cyclin B Metaphase Anaphase Metaphase Checkpoint chromosome attachment to mitotic spindles M G2 G1 S tension at kinetichore Metaphase APC APC inactive active Mad2 Securin Separase Cohesin promotes chromosome separation CELL CYCLE IS COMPLEX! THERE ARE MANY INCOMING TRIGGERS THE DETECTION OF DNA DAMAGE IS VERY COMPLEX!
