TZAPping Telomeres Shorter

Graduate Division

Our DNA fits into our cells by tightly coiling into structures called chromosomes. During cell division, the machinery that is responsible for DNA replication cannot replicate the very ends of chromosomes, so some genetic information may be lost during each replication. This does not occur, however, because of telomeres.

Telomeres are repetitive sequences of six DNA bases, TTAGGG, at the end of chromosomes. They prevent valuable DNA that codes for proteins from being lost during replication because the repetitive telomeric DNA is gradually lost instead.

Chromosomes need to be protected at their ends or they will fuse with other chromosomes, which is unfavorable for the health and normal function of a cell.

In the majority of human cells, telomeres become progressively shorter after each cell division. Eventually, telomeres will get too short and trigger a warning in the cell that prevents it from dividing. This is called replicative senescence, and as humans age the number of senescent cells in the body increases.

If old cells stop growing because they have short telomeres, what happens when the telomeres are lengthened?

In some human cells telomere length is replenished by a protein complex called telomerase. According to a 2011 study in mice, reactivating telomerase rejuvenates old tissues.

So why don't scientists just reactivate telomerase and prevent people from aging?

Reactivating telomerase is associated with cancer because it allows old cells, which are more likely to have mutations in their DNA or be genomically unstable, to replicate and generate additional copies of mutated cells.

Nearly all cancer cells have found a way to continually re-lengthen critically short telomeres or maintain them in a long form, which prevents the cell from entering replicative senescence and makes it immortal.

Detailed knowledge of how telomeres shorten and lengthen is very important for understanding how we age and how cancer develops. Subsequently, these insights may provide ways to kill immortal cancer cells and safely slow, or even reverse, aging.

Researchers from the Salk and Scripps Institutes in San Diego, CA published a paper this week that identified a new protein that is involved in controlling the length of telomeres.

The authors found that TZAP, short for telomeric zinc finger-associated protein, specifically localizes to telomeres in cells that do and do not express telomerase. TZAP localized to telomeres in similar amounts to TRF1, another protein known to bind telomeres.

TZAP is the first new protein found to localize to telomeres that does not interact with and is not part of the shelterin complex, which helps protect telomeres. Rather, TZAP competes for telomeric binding with members of the shelterin complex, like TRF2.

Long telomeres and short telomeres have the same amount of shelterin complex binding, meaning in long telomeres the density of shelterin binding is lower. Interestingly, the authors determined TZAP preferentially binds longer telomeres with less-dense shelterin binding.

Furthermore, when TZAP binds long telomeres in the absence of telomerase, the telomeres rapidly grow shorter in a process known as telomere trimming.

As previous studies have shown that telomeric trimming is particularly important in maintaining embryonic stem cell (ESC) telomere length, the authors wanted to investigate the role of TZAP in these cells.

They deleted TZAP from embryonic stem cells using precise genome editing and found that TZAP-negative cells had much longer telomeres. Reintroducing TZAP to the TZAP-negative ESCs shortened their telomeres.

This study provides additional insight into how telomere length is maintained, a mechanism that could be targeted to help us better understand human lifespan and cancer risk.