6 replies to this topic

[Tom Andre F. (ex shinobi)]

The full article: http://www.genengnew...ength/81251981/

[elfanjo]

New Enzyme Discovered for Sustaining Telomere Length
Click Image To Enlarge +

Researchers developed a novel assay to identify telomere length regulators and showed that ATM inhibition shortens telomeres, whereas ATM activation elongates telomeres. [Lee et al., 2015, Cell Reports 13, 1–10]
In the early years of molecular biology research, scientists studying chromosomal structure and composition noticed that the terminal ends of chromosomes, called telomeres, would gradually become shorter with each successive round of cellular replication. This process would continue until the chromosome reached a certain length, ultimately becoming unstable and causing the cell to die. Conversely, the scientists noticed that for certain genetic disorders, such as cancer, an abnormally long telomere length led to genome anomalies that were closely associated with the cancer phenotype.

In 1984, researchers Elizabeth Blackburn, Ph.D., and Carol Greider, Ph.D., who was at the time a graduate student in Dr. Blackburn’s laboratory, discovered the telomerase enzyme, which was responsible for maintaining the appropriate length of telomerase after chromosomal replication. Drs. Blackburn and Greider would go on to be awarded the 2009 Nobel Prize in Physiology and Medicine, along with Jack Szostak, Ph.D. for their work on molecular mechanisms of the telomerase enzyme.

Yet, even during their seminal work, the investigators quickly realized that other molecules besides telomerase must be involved in maintaining the protective caps at the end of chromosomes. Now, researchers at Johns Hopkins report uncovering the role of an additional enzyme crucial to telomere length and say the novel method they could be used to speed discovery of other proteins and processes that are involved in telomere stability.

"We've known for a long time that telomerase doesn't tell the whole story of why chromosomes' telomeres are a given length, but with the tools we had, it was difficult to figure out which proteins were responsible for getting telomerase to do its work," explained Dr. Greider, professor, and director of molecular biology and genetics in the Johns Hopkins Institute for Basic Biomedical Sciences.

The findings from this study were published recently in Cell Reports through an article entitled “ATM Kinase Is Required for Telomere Elongation in Mouse and Human Cells.”

Understanding the mechanisms that are needed to lengthen telomeres has broad health implications, since shortened telomeres have been implicated in aging and diseases as diverse as lung and bone marrow disorders, while overly long telomeres are linked to cancer. Cells need a well-tuned process to keep adding the right number of building blocks back onto telomeres over an organism's lifetime.

Unfortunately, until recently, the methods researchers used to study telomere length were extremely time-consuming, often taking months of work to study cells grown in vitro, searching for detectable differences in telomere length. However, Dr. Greider’s team developed a new tool for measuring telomere length in yeast. The idea was to artificially cut mammalian cells' telomeres and then detect elongation by telomerase—a test that would take less than a day, and could be performed even if the blocked proteins were needed for cells to divide.

The new test, dubbed addition of de novo initiated telomeres (ADDIT) was used to observe an enzyme long suspected to be involved in telomere maintenance, ATM kinase. "ATM kinase was known to be involved in DNA repair, but there were conflicting reports about whether it had a role in telomere lengthening," noted Dr. Greider.

The Hopkins researchers blocked the enzyme in lab-grown mouse cells and used ADDIT to find that it was indeed needed to lengthen telomeres. They confirmed their result by using the old, three-month-long telomere test, which lead to the same outcome.

Additionally, the team also found that in normal mouse cells, a drug that blocks an enzyme called PARP1 would activate ATM kinase and spur telomere lengthening. This finding has the potential to impact drug-based telomere elongation for treating short-telomere diseases, such as bone marrow failure.

Dr. Greider and her team were excited by their findings and plan to use ADDIT to find out more about the telomere-lengthening biochemical pathway that ATM kinase participates.

"The potential applications are very exciting," stated lead author Stella Lee, Ph.D., postdoctoral fellow in Dr. Greider’s laboratory. "Ultimately ADDIT can help us understand how cells strike a balance between aging and the uncontrolled cell growth of cancer, which is very intriguing."

[alc]

This study reinforce the path that Michael Fossel, Bill Andrews & others like them are taking.

 

Of course we will see couple hardliners contesting this ... but the science moves on.

 

One of the things that confused (some) researchers was the cancer issue.

 

Based on

the data/info we seen, seems like cancer is using the telomere-lengthening mechanism to

become immortal.

 

How interesting? Why?

 

But the studies, point out at a "parallel" mechanism, meaning (some) cancers use telomerase for that, BUT

adding telomerase (to lengthen telomeres), not (necessarely) result in cancer.

 

Of course we need more serious studies (in human, if possible) to prove/not this.

 

[Logic]

Iporuru:

I’m not sure PARP-1 inhibition is a good idea in the light of this:

http://jpet.aspetjou...e&submit=Submit

“Genotoxins damage DNA and cause DNA strand breaks. These DNA breaks are sensed by a DNA repair system, which includes PARPs and a sirtuin, SIRT6. The activation of PARP, in particular, causes a rapid synthesis of poly(ADP-ribose) at the site of the strand break, and when this system is overactivated, it can significantly deplete cellular NAD+.
(...)
A considerable body of evidence implicates NAD+ metabolism as important for the maintenance of genome stability (Hassa et al., 2006). Consistent with a role for PARP in DNA repair, PARP–/– animals exhibit hypersensitivity to alkylating agents and ionizing radiation (Decker and Muller, 2002) and that some cancers are found to have reduced PARP activities (Decker and Muller, 2002).”
(...)
In vitro results indicate that PARP-1 inhibition leads to delayed DNA repair, particularly base excision repair (Hassa et al., 2006). Consistent with a role for PARP in DNA repair, PARP–/– animals exhibit hypersensitivity to alkylating agents and ionizing radiation (Hassa et al., 2006). Some data appear to indicate that a normal if not an augmented NAD+ level in tissues aids in DNA repair and may reduce carcinogenesis. Some hints that this may be true are found in epidemiological studies that show that PARP-1 activity levels are lower in families predisposed to cancer (Decker and Muller, 2002) and that some cancers are found to have reduced PARP activities (Decker and Muller, 2002). Another finding of interest is that PARP activity may be generally higher in long-lived people, suggesting that PARP activity levels may have an antiaging effect (Decker and Muller, 2002).”

http://www.longecity...ndpost&p=634256

 

Its possible that by inhibiting PARP1 these researchers increased NAD+ and that is what activated ATM kinase..?

 

Also PARP1 activation kills cancerous cells IIRC.

Edited by Logic, 22 November 2015 - 03:06 PM.

[xEva]

ATM stands for

 

wiki : The protein is named for the disorder ataxia telangiectasia caused by mutations of ATM.

 

Ataxia telangiectasia mutated (ATM) is a serine/threonine protein kinase that is recruited and activated by DNA double-strand breaks. It phosphorylates several key proteins that initiate activation of the DNA damage checkpoint, leading to cell cycle arrest, DNA repair or apoptosis. Several of these targets, including p53, CHK2, BRCA1, NBS1 and H2AX are tumor suppressors.

One feature of the ATM protein is its rapid increase in kinase activity immediately following double-strand break formation.

 

A functional MRN complex is required for ATM activation after double strand breaks (DSBs). 

MRN complex == NBN == NBS1 == nibrin

 

 

NBS1 is one of 6 enzymes required for this error prone DNA repair pathway. It is over-expressed in some cancers.

Cancers are very often deficient in expression of one or more DNA repair genes, but over-expression of a DNA repair gene is less usual in cancer. Ordinarily, deficient expression of a DNA repair enzyme results in increased un-repaired DNA damages which, through replication errors, lead to mutations and cancer. However, NBS1 mediated MMEJ repair is highly inaccurate, so in this case, over-expression, rather than under-expression, apparently leads to cancer.

[Tom Andre F. (ex shinobi)]

Is there any way or strategy to increase NBS1 then ?

 

I think its like with htert, we need to also activate p53 in the same time. a gene to make cell immortal and another to shut down the iregularity.

[Logic]

Metformin Upregulates ATM Kinase
I am not sure if Pterostilbene has the same MOA?

Caffeine downregulates ATM Kinase.