The natural ends of chromosomes appear alarmingly like broken DNA, much as a snapped spaghetti strand is difficult to distinguish from its intact counterparts. Yet every cell in our bodies must have a way of differentiating between the two because the best way to protect the healthy end of a chromosome also happens to be the worst way to repair damaged DNA.
Consider the enzyme telomerase, which is responsible for maintaining protective telomeres at the natural ends of chromosomes. Were telomerase to seal off a broken strand of DNA with a telomere, it would prevent further repair of that break and delete essential genes. Now, a new study in Science describes how cells avoid such mishaps. These findings show that telomerase can indeed run amok, adding telomeres to damaged DNA, and would do so were it not for the ATR kinase, a key enzyme that responds to DNA damage.
"Telomerase is a good thing because it maintains our telomeres, but it should only be acting at the natural ends of chromosomes. It is very bad if it acts at double-stranded DNA breaks because it can lead to the loss of all genes distal to the break," says the senior author. "This detrimental aspect of telomerase is inhibited by the ATR kinase, which, among its many talents, also keeps telomerase away."
The discovery may help optimize CRISPR techniques and could inform the study of cancer.
One of the earliest hints that telomerase could, absent proper controls, act on damaged DNA appeared in 1990, when a study in Nature reported that an individual suffering from α-thalassemia had a broken DNA end with telomeric DNA added to it. But whether telomerase was to blame for this rogue telomere, and how healthy cells prevented this from happening, remained unclear. An MD/PhD student in the lab, scoured the literature for similar cases and set out to determine whether telomerase was the culprit.
The authors first broke bits of human DNA with Cas9, the cutting component of the CRISPR gene-editing tool, and established that telomerase creates "neotelomeres" on broken DNA. Having established telomerase as driving the formation of neotelomeres, the authors then began interrogating various molecular pathways to determine what prevents telomerase from interfering with DNA repair under normal circumstances and ultimately found that disrupting ATR kinase signaling increases neotelomere formation and demonstrated that when ATR is activated at DNA breaks, it prevents telomerase from ruining the repair.
"It's a race between telomerase and ATR," the author says. "Telomerase needs the DNA end to be chewed in to form its single-stranded substrate. But at the same time, the single-stranded DNA is what activates ATR.”
The findings have immediate implications for researchers and clinicians involved in CRISPR gene editing. Kinzig and colleagues found that telomerase can add telomeric DNA to the DNA ends made during CRISPR editing. This could potentially lead to insertion of telomeric DNA or formation of a telomere at the site where CRISPR editing was intended. “The CRISPR field now is aware of this and can take steps to prevent this unwanted outcome,” the senior author said.
In the long term, the lab plans to focus on how the findings relate to cancer. Telomerase is activated in most human cancers, and it is thought that this helps cancers maintain their telomeres, effectively becoming immortal. The authors speculate that neotelomere formation may allow cancers to tolerate processes that generate broken chromosomes, such as deficiencies in BRCA1.
“We are now testing whether neotelomere formation indeed helps cells deal with the genome instability that plagues cancer cells,” said the senior author. “We’ll see. Much remains to be learned.”
Latest News
Mechanism of sugar signalin…
By newseditor
Posted 19 May
How does the brain turn wav…
By newseditor
Posted 19 May
A trial HIV vaccine trigger…
By newseditor
Posted 19 May
AI to predict DNA methylati…
By newseditor
Posted 19 May
Hyperactive platelets from…
By newseditor
Posted 19 May
Other Top Stories
A brain circuit inhibits food intake during nausea
Read more
Link between dietary choices and brain health
Read more
Circadian clock synchronization between brain and muscle prevents m…
Read more
Genomic regions with epigenetic modifications linked to ALS progres…
Read more
Males burn more fat, while females recycle it during exercise
Read more
Protocols
Breast cancer-on-chip for p…
By newseditor
Posted 16 May
Methods for making and obse…
By newseditor
Posted 15 May
Mime-seq 2.0: a method to s…
By newseditor
Posted 13 May
Improved detection of DNA r…
By newseditor
Posted 09 May
Single-cell adhesive profil…
By newseditor
Posted 07 May
Publications
Molecular mechanism of treh…
By newseditor
Posted 19 May
Hue selectivity from recurr…
By newseditor
Posted 19 May
Vaccine induction of hetero…
By newseditor
Posted 19 May
Brain border-associated mac…
By newseditor
Posted 19 May
Inhibition of fatty acid up…
By newseditor
Posted 19 May
Presentations
Hydrogels in Drug Delivery
By newseditor
Posted 12 Apr
Lipids
By newseditor
Posted 31 Dec
Cell biology of carbohydrat…
By newseditor
Posted 29 Nov
RNA interference (RNAi)
By newseditor
Posted 23 Oct
RNA structure and functions
By newseditor
Posted 19 Oct
Posters
A chemical biology/modular…
By newseditor
Posted 22 Aug
Single-molecule covalent ma…
By newseditor
Posted 04 Jul
ASCO-2020-HEALTH SERVICES R…
By newseditor
Posted 23 Mar
ASCO-2020-HEAD AND NECK CANCER
By newseditor
Posted 23 Mar
ASCO-2020-GENITOURINARY CAN…
By newseditor
Posted 23 Mar