BMS 141 Lecture 4: Telomere & Telomerase (Fall 2024) PDF

BMS: 141 Lecture No: 4 Title: Telomere & telomerase Instructor Name: Dr. Amira Abdel Haleem Medicine and Surgery Program Fall 2024  Intended Learning Outcomes of lecture At the...

BMS: 141 Lecture No: 4 Title: Telomere & telomerase Instructor Name: Dr. Amira Abdel Haleem Medicine and Surgery Program Fall 2024  Intended Learning Outcomes of lecture At the end of this lecture, the students will be able to: 1. Explain end replication problem 2. Explain molecular mechanism of telomerase  Telomeres Def.: Telomeres are complexes of noncoding DNA plus proteins located at the ends of linear chromosomes. Function: Telomeres may be viewed as mitotic clocks in that their length in most cells is inversely related to the number of times the cells have divided. The study of telomeres is providing insight into the biology of aging and cancer.  Telomeres (Cont.,) They maintain the structural integrity of the chromosome Preventing attack by nucleases. Allow repair systems to distinguish a true end from a break in dsDNA.  Telomeres (Cont.,) Structure: In humans, telomeric DNA consists of several thousand tandem repeats of a noncoding hexameric sequence, AG3T2, base-paired to a complementary region of Cs and As. The GT-rich strand is longer than its CA complement, leaving ssDNA a few hundred nucleotides in length at the 3'-end. The single-stranded region is thought to fold back on itself, forming a loop structure that is stabilized by protein.  End Replication Problem Eukaryotic cells face a special problem in replicating the ends of their linear DNA molecules. Following removal of the RNA primer from the extreme 5'-end of the DNA strand, there is no way to fill in the remaining gap with DNA. Consequently, in most normal human somatic cells, telomeres shorten with each successive cell division. Once telomeres are shortened beyond some critical length, the cell is no longer able to divide and is said to be senescent.  End Replication Problem (Cont.,) In germ cells and other stem cells, as well as in cancer cells, telomeres do not shorten and the cells do not senesce. This is a result of the presence of a ribonucleoprotein, telomerase, which maintains telomeric length in these cells.  Telomeres and telomerase Telomerase is an unusual enzyme contains a protein that acts as a reverse transcriptase, and a short piece of RNA that acts as a template. The CA-rich RNA template base-pairs with the GT-rich, single- stranded 3'-end of telomeric DNA. The reverse transcriptase uses the RNA template to synthesize DNA in the usual 5'→3' direction, extending the already longer 3'-end.  Telomeres and telomerase (Cont.,) Telomerase then translocates to the newly synthesized end, and the process is repeated. Once the GT-rich strand has been lengthened, primase can use it as a template to synthesize an RNA primer. The RNA primer is extended by DNA polymerase, and the primer is removed. Clinical significance of telomerase Development and utilization of telomerase inhibitors could play a role in treatment of cancer.  References for further readings Lippincott Illustrated Review Integrated system Lippincott Illustrated Review 6th edition Oxford Hand book of Medical Science 2nd edition THANK YOU