Molecular Clues to Physiological and Premature Ageing Revealed

Inappropriate upregulation of genes on chromosomes 2 and 5 (stained pink and green) in anaplastic large cell lymphoma  leads to reorganization of surrounding DNA and its regulatory proteins, resulting in the spatial convergence of these two chromosomes within the nucleus.

Loss of RBBP4 protein occurs in accelerated and physiological ageing. Immunofluorescence staining of skin cells from a (top) young, (middle) premature ageing /Hutchison-Gilford Progeria Syndrome patient and (bottom) a normally aged individual. RBBP4 is lost in aged cells. Arrowheads point to cell nuclei.

There are many theories about the molecular basis of ageing. One of the most popular ones postulates that organisms age by accumulating damage to their tissues, cells, and molecules. On the cellular level, ageing is associated with progressive changes in chromatin (a combination of DNA and proteins that makes up chromosomes). These changes include loss of chromatin structure, loss and/or modification of essential proteins, and accumulation of DNA damage.

Many chromatin defects that gradually appear in physiological ageing are also observed in children affected with the premature ageing disease Hutchison-Gilford Progeria Syndrome (HGPS). Thus, studying cells derived from HGPS patients helps scientists understand the molecular basis of normal ageing. Using HGPS cells as a model, Gianluca Pegoraro, Ph.D., a postdoctoral fellow working with Tom Misteli, Ph.D., in the Cell Biology of Genomes Group in the CCR Laboratory of Receptor Biology and Gene Expression, and collaborators identified several key molecular players that affect ageing-related chromatin changes. The results of their study were published in a recent issue of Nature Cell Biology.

The disease-causing factor in HGPS is a genetic mutation that leads to the production of a shortened form of the protein lamin A, also known as progerin. Lamin A is an architectural protein which supports the membrane that surrounds the cell nucleus. Cells with a mutated lamin A protein have a disorganized nuclear membrane, accumulation of chromatin defects, and impaired repair of damaged DNA. Dr. Pegoraro and his coauthors found that the levels of two key nuclear proteins, RBBP4 and RBBP7 were lower in cells from HGPS patients than in those from healthy volunteers. This loss of RBBP4 and RBBP7 protein was dependent on the presence of progerin and reduction of the cellular levels of RBBP4 and RBBP7 contributed to changes in chromatin structure and increased DNA damage, which are typically observed in HGPS and normal ageing.

RBBP4 and RBBP7 proteins are components of various protein machineries important for establishing chromatin structure and repairing DNA damage, including the nucleosome remodeling and deacetylase NURD complex. Testing confirmed that several subunits of NURD are absent from HGPS cells as well as from cells of normally aged individuals. These findings suggest that loss of NURD is a feature of both premature and normal ageing. Further research is needed to determine how loss of NURD components occurs.

Based on the results of this study, Dr. Pegoraro and colleagues propose a molecular model of ageing. The first step in the initiation of ageing-associated chromatin defects is loss of chromatin proteins such as RBBP4 and RBBP7 proteins, which leads to changes in chromatin structure. These alterations then result in higher levels of unrepaired DAN lesions. The study suggests that maintenance of chromatin and the genome is a critical determinant of aging.

Summary Posted: 11/2009


Nat Cell Biol. 2009 Oct;11(10):1261-7 PubMed Link