Question

What are telomeres? What challenge do they present to DNA replication? How is this dealt with? How might this be related to aging?

Answer 1

Telomeres are complexes of noncoding DNA plus proteins located at the ends of linear chromosomes. They maintain the structural integrity of the chromosome, preventing attack by nucleases, and allow repair systems to distinguish a true end from a break in dsDNA. In humans, telomeric DNA consists of several thousand tandem repeats of a noncoding hexameric sequence, AGGGTT, 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.

Following removal of the RNA primer from the extreme 5' end of the lagging 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.

A special ribonucleoprotein is present, in germ cells or cancer cells, which is known as telomerase. This complex contains a protein (Tert) that acts as a reverse transcriptase and a short piece of RNA (Terc) 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. Telomerase then translocates to the newly synthesized end, and the process is repeated. Once the GT-rich strand has been lengthened, primase activity of DNA pol α can use it as a template to synthesize an RNA primer. The RNA primer is extended by DNA pol α, and then removed.

A cell can only thrive, when its DNA is intact. As telomeres get shortened in every mitosis occurs, there will be a time when the DNA will reach to a critical length, and the cell cannot divide and thrive. This happens to with age if, leading to death of cells in ageing.