Genes that Underlie the

Human Aging Process


We all know what aging looks like, and we become more familiar with the many effects of this process as we age ourselves. Despite our general familiarity with symptoms of aging like wrinkled skin, greying and loss of hair, increased incidence of cancer among many others, very little is know about the cellular and molecular processes that cause these age-related symptoms.  Our work is directed at understanding the molecular and cellular processes that underlie these outward effects of aging. 


Werners Syndrome
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Research of aging in at the molecular level has focused on several very rare human genetic disorders (syndromes) that cause a subset of age-related conditions to arise prematurely. Such conditions where symptoms resembling aging arise at an early age are known as progeria or progeria syndromes. Unique among such premature aginig syndromes is Werners syndrome (WS), which has no symptoms during childhood but rapid aging begins to appear in early adulthood. Moreover, the spectrum of symptoms associated with Werners syndrome most closely mimic that of genuine aging in humans. Because Werners syndrome is a genetic disorder that is our best model for accelerated aging, we have focused our efforts on understanding the the structure and function of the WRN protein that underlies this disease. We are interested in establishing what this protien does within the cell and how these functions cause the early onset of such a broad spectrum of aging symptoms. By understanding how WRN functions in our cells, we hope to gain fundamental insights into the molecular and cellular processes that 'cause' aging in humans.  By understanding the causes of aging, we then can begin to think about ways to mitigate the adverse health effects associated with human aging.
                                                                                                                                                       

Werners Syndrome Protein

The genetic defect in Werners syndrome patients that causes the premature onset of aging alters the function of an enzyme called Werners protein, or WRN for short. The WRN protein is a multifunctional enzyme that has three known functional capabilities; 1) it can unwind the DNA double helix into two separate single-strands of DNA ('helicase activity'), 2) it can chew up DNA one base at a time from broken ends ('exonuclease activity'), and 3) it can put two single-stranded pieces of DNA together to make double-stranded DNA, the opposite of helicase activity ('annealing activity'). How the loss of this protein and its associated functions in cells causes rapid aging in human patients is unknown. We are working to understand the functions and structure of this enzyme to get clues as to what it does in cells and connect the functions of WRN with what we see as symptoms of aging.
        Our interest in these problems began with an observation while studying the process of DNA repair in human cells, when we found a functional interaction between the WRN protein and the DNA-dependent protein kinase (Yannone et al 2001). This observation linked the repair of DNA double-strand breaks to the function of WRN in the cell and we thought may lead to a better understanding of the function of WRN and how it related to aging. From that point we have been pursuing a 'structure-function' approach to this problem. More specifically, we have been working to understand the exact structure of WRN and how this 'little machine' is put together so we can begin to understand what it is doing in the cell. As part of these efforts we solved the atomic-resolution structure of the human WRN nuclease domain (Perry et al 2006). More recently we identified a part of the protein that holds together three and six WRN molecules to form a ring-like structure (Figure & Perry et al 2010). By understanding how and what the WRN enzyme does, we hope to better understand the cellular processes and the biochemical reactions that influence the aging process in humans. 


Our Work In the News:

http://www.lbl.gov/Science-Articles/Archive/LSD-WRN-secrets.html 


Our Relevant Publications:


The DNA repair endonuclease XPG interacts directly and functionally with the WRN helicase defective in Werner syndrome.

Trego KS, Chernikova SB, Davalos AR, Perry JJ, Finger LD, Ng C, Tsai MS, Yannone SM, Tainer JA, Campisi J, Cooper PK.

Cell Cycle. 2011 Jun 15;10(12):1998-2007. Epub 2011 Jun 15.


Identification of a coiled coil in werner syndrome protein that facilitates multimerization and promotes exonuclease processivity.

Perry JJ, Asaithamby A, Barnebey A, Kiamanesch F, Chen DJ, Han S, Tainer JA, Yannone SM.

J Biol Chem. 2010 Aug 13;285(33):25699-707. Epub 2010 Jun 1.



Telomere dysfunction and cell survival: roles for distinct TIN2-containing complexes.

Kim SH, Davalos AR, Heo SJ, Rodier F, Zou Y, Beausejour C, Kaminker P, Yannone SM, Campisi J.

J Cell Biol. 2008 May 5;181(3):447-60. Epub 2008 Apr 28.mpisi J., J Cell Biol. 2008 May 5;181(3):447-60. Epub 2008 Apr 28.  

 

                                                  

WRN exonuclease structure and molecular mechanism imply an editing role in DNA end processing.

Perry JJ, Yannone SM, Holden LG, Hitomi C, Asaithamby A, Han S, Cooper PK, Chen DJ, Tainer JA.

Nat Struct Mol Biol. 2006 May;13(5):414-22. Epub 2006 Apr 23.



Novel function of the flap endonuclease 1 complex in processing stalled DNA replication forks.

Zheng L, Zhou M, Chai Q, Parrish J, Xue D, Patrick SM, Turchi JJ, Yannone SM, Chen D, Shen B.

EMBO Rep. 2005 Jan;6(1):83-9.


Werner syndrome protein is regulated and phosphorylated by DNA-dependent protein kinase.

Yannone SM, Roy S, Chan DW, Murphy MB, Huang S, Campisi J, Chen DJ.

J Biol Chem. 2001 Oct 12;276(41):38242-8. Epub 2001 Jul 27.