How to prevent and cure cancer and live forever Cellular repair of DNA damage, prevention of damage and how cells become immortal

DNA MUTATIONS CAN RESULT FROM INCORRECT MATCHING OF BASE PAIRS H lost off N on Cytosine H lost off N on Guanine Error rate due to insertion of incorrect base pair by DNA polymerase is approximately 1 in 104.

DNA MUTATIONS CAN RESULT FROM INCORRECT MATCHING OF BASE PAIRS TAUTOMERIC PROTON SHIFTS Link to insertion mutation animation.

DNA POLYMERASE REDUCES ERRORS BY PROOFREADING (MISMATCH REPAIR)

DNA POLYMERASE PROOFREADING (MISMATCH REPAIR) REDUCES ERROR RATE TO 1 IN 108 BASES Link to proofreading animation

PROOFREADING ANIMATION

How does cell know which is parent strand in mismatch repair? In some cases original parent strand is chemically “marked” by methyl groups. In some cases the enzymes are forced to “guess” and guess wrong. Link to methylation mismatch repair NOT ON TEST

DNA MUTATIONS ARE CAUSED EXPOSURE TO RADIATION, CHEMICAL AND INFECTIOUS AGENTS SUCH AS VIRUSES OR CERTAIN BACTERIA MUTATIONS IN DNA REPAIR SYSTEM ENZYMES, INCLUDING TUMOR SUPRESSION AND APOPTOSIS GENES GREATLY INCREASES CANCER RISK

Figure 16.17 Nucleotide excision repair of DNA damage EXCISION REPAIR -REMOVE AND REPLACE DAMAGED DNA SECTION ON TEST Note repair enzymes: Link to Thymine dimer repair animation

Ends Replication Problem Problem of copying the 3’ parent end (lagging strand) in eukaryotes Link to summanas video

3’ 5’ OH 3’ 5’ OH 5’ 3’ OH 5’ 3’ OH 5’ 3’ 5’ 3’ LAGGING STRAND SYNTHESIS AT 3’ PARENT END DNA POL I Daughter Leading Strand DNA 3’ 5’ OH 3’ 5’ OH 5’ 3’ OH 5’ 3’ OH 5’ 3’ 5’ 3’ Parent Strand

3’ 5’ OH 3’ 5’ OH 5’ 3’ OH 3’ 5’ OH 5’ 3’ OH 5’ 3’ 5’ 3’ LAGGING STRAND SYNTHESIS AT 3’ PARENT END DNA POL I Daughter Leading Strand DNA 3’ 5’ OH 3’ 5’ OH 5’ 3’ OH 3’ 5’ OH 5’ 3’ OH 5’ 3’ 5’ 3’ Parent Strand

LAGGING STRAND SYNTHESIS AT 3’ PARENT END DNA POL I Daughter Leading Strand DNA 3’ 5’ OH 5’ 3’ 5’ 3’ Parent Strand Since DNA polymerase I needs a template to bind to and an existing strand to elongate, there is a gap in the daughter strand opposite the 3’ parent strand that cannot be filled.

DNA polymerase I removes RNA primer Fig. 16-19 5 Ends of parental DNA strands Leading strand Lagging strand DNA polymerase I removes RNA primer 3 Last fragment Previous fragment RNA primer Lagging strand 5 3 Parental strand Removal of primers and replacement with DNA where a 3 end is available DNA Pol I cannot add to 5’ end, only 3’ end 5 3 Second round of replication 1 daughter is shortened and 1 has 3’ overhang in next round of replication 5 New leading strand 3 New lagging strand 5 3 Further rounds of replication Shorter and shorter daughter molecules

Replication in Eukaryotes occurs at multiple origin points within the DNA but never at the ends; Process of lagging strand synthesis results in incomplete ends on 3’ parent ends of chromosome

TELOMERES ARE NONSENSE REPEAT SEQUENCES ATTACHED TO ENDS OF CHROMOSOMES THAT CAN BE SHORTENED WITHOUT DAMAGING CODING REGIONS OF CHROMOSOMES. Video link Human telomeres are approximately 2000 bp in length (≈330 TTAGGG repeats); Cells can undergo about 70-80 divisions before chromosome damage causes death

Link to Telomere animation Elizabeth Blackburn Carol Grei Shared 2009 Nobel Prize in Medicine for discovery of telomeres (along with Jack W. Szostak)

Figure 16.19b Telomeres and telomerase

Figure 16.19b Telomeres and telomerase

Addition of telomeres is catalyzed by enzyme telomerase Link to telomere animation

Eternal Life from expression of telomere genes? In theory, our cells could continue to divide indefinitely if the telomere gene which is not normally expressed in adult cells could be switched on. The experiment has been tried in mice. It does extend health and life, in one Harvard study it actually seem to reverse some aging processes. In Humans increasing telomerase activity is high associated with increased cancer risk.

Stem cells and cancer have active telomerase; Differentiated cells do not express telomerase gene

Telomerase Inhibitors are potential anti-cancer drugs Cancer cells are cells with rapid, uncontrolled replication. Cancer cells apparently can undergo unlimited cell divisions. Rate of Growth of Tumors could be slowed by telomerase inhibitors ; after many generations cancer cells would eventually die after telomeres become too short. Note: Telomeres in cancer cells are typically shorter than those in normal cells.