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A false color transmission electron microscopy image showing a cell's nuclear envelope (red), chromatin (green) and nucleolus (blue). Hutchinson-Gilford Progeria Syndrome has been linked to DNA damage.

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Stopping premature aging in its tracks

20 Mar 2020

DNA damage associated with premature aging in Hutchinson-Gilford Progeria Syndrome can be prevented if the abnormal protein progerin is removed before DNA replication.

Every February 29th, a date befitting the rarity of the diseases it highlights, Rare Disease Day is held to raise awareness for rare diseases around the world. Although rare, these diseases can be devastating, such as in the case of Hutchinson-Gilford Progeria Syndrome (HGPS), a genetic condition that causes children to age—and die—prematurely. Importantly, these diseases provide a unique glimpse into potential mechanisms that trigger cell and organismal aging.

HGPS is caused by a mutation in the LMNA gene, creating an abnormal version of the Lamin A protein called progerin. Progerin is known to cause signs of accelerated aging such as DNA damage and the loss of heterochromatin, a densely packed form of DNA located near the nuclear lamina. However, it was unclear if DNA damage and heterochromatin loss were linked and whether therapeutic interventions that remove progerin would be able to rejuvenate these cells.

A team from the Skin Research Institute of Singapore (SRIS) and the Institute of Medical Biology (IMB) has now shown that heterochromatin loss is actually a prerequisite for progerin-mediated DNA damage, and that DNA damage can be prevented altogether if progerin is removed before the cells replicate their DNA.

Using immunofluorescence microscopy to measure the levels of heterochromatin, DNA damage and progerin in cells arrested at different stages of the cell cycle the team found that progerin-expressing cells in the non-dividing (G1) stage of the cell cycle lost heterochromatin but did not accumulate DNA damage. In contrast, progerin caused DNA damage exclusively during the late stages of DNA replication and preferentially in cells with low levels of heterochromatin.

This discovery is in line with the team’s previous findings that progerin-induced DNA damage can be alleviated with telomerase. “Telomerase is active only during DNA replication,” explained study corresponding author Oliver Dreesen, a Principal Investigator at SRIS. “This made me think that progerin-induced DNA damage may have happened during replication—or else telomerase would not have been able to prevent it. This idea led us to investigate when progerin causes DNA damage, and indeed it’s during the very late stages of replication.”

“Our data also shows that removing progerin from quiescent cells would restore heterochromatin levels. Importantly, based on the assays we used, these cells now behave like cells that never were exposed to progerin,” said Dreesen.

“This study provides a proof of concept that removing progerin from non-dividing cells or tissues would leave no permanent damage and fully restore cell function,” said Brian Kennedy, Director of National University Health System Centre for Healthy Ageing in Singapore. “This takes us one stage closer in therapeutic development.”

The A*STAR-affiliated researchers contributing to this research are from the Skin Research Institute of Singapore (SRIS) and the Institute of Medical Biology (IMB).

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References

Heterochromatin loss as a determinant of progerin‐induced DNA damage in Hutchinson–Gilford Progeria. Aging Cell, 19:e13108 (2020) | article

About the Researcher

Oliver Dreesen

Principal Investigator

Skin Research Institute of Singapore
Oliver Dreesen received his PhD from the Rockefeller University in New York City, where he studied the structure and function of telomeres and telomerase in Trypanosoma brucei. In 2009, he joined the Institute of Medical Biology in Singapore to study telomeres during cellular reprogramming and in rare genetic human diseases. Dreesen was promoted to Project Leader in 2013, and in 2016, to Principal Investigator and Head of the Laboratory for Cell Aging at the Skin Research Institute of Singapore. He is currently serving as President of the Skin Research Society (Singapore).

This article was made for A*STAR Research by Wildtype Media Group