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Melanoma is the deadliest form of skin cancer.
Metastatic melanoma has a survival rate of only six to nine months after diagnosis. In 2013, metastatic melanoma was responsible for more than 9,000 deaths in the U.S. in 2013.
Melanoma arises from cells called melanocytes that are located within your skin. Melanocytes synthesize a brownish black pigment called melanin and distribute it to surrounding cells. This is how your skin tans.
Melanocytes also have a nuclear compartment containing important genetic material called DNA. Melanoma arises when a melanocyte acquires sufficient amounts and types of DNA damage that is not repaired. Each of these damages can result in permanent change in the DNA, called a mutation.
The ultraviolet portion of sunshine is a major environmental risk factor in the development of melanoma. When we are in the sunlight, we are exposed to ultraviolet radiation, which induces the ‘tanning response’ in our skin cells. The first action of this tanning response is for skin cells called keratinocytes to synthesize a hormone called alpha melanocyte stimulating hormone. This hormone binds to a protein on the surface of melanocytes called MC1 receptor and triggers melanin synthesis.
On a rainy day an umbrella is a protective shield from the rain. Similarly, melanin forms a protective shield for your DNA from ultraviolet rays. Some people with inherited variations in the MC1 receptor are not very good at synthesizing melanin when they are exposed to ultraviolet radiation, therefore are at higher risk for melanoma. People born with these MC1 receptor variations usually have red hair, easily freckle, and are unable to tan.
There are other variations in the MC1 receptor that do not affect melanin synthesis but may instead cause failure to repair DNA. DNA exposed to ultraviolet radiation undergo specific types of damage that are repaired by specific DNA repair pathways. If correct repair of ultraviolet-induced DNA lesions does not occur, then permanent mutations are introduced into the DNA.
Specific mutations cause transformation of normal melanocytes to melanoma. DNA within normal human cells is in very long strands. These long strands of DNA are wrapped around proteins called histones to become a supercoiled compact structure that fits snugly into the nuclear compartment of the cell. This structure resembles beads on a string and is called chromatin.
Our scientific team at the University of Toledo is studying a chromatin remodeling protein complex called the SWI/SNF complex. In order for other proteins to interact with the genetic information within chromatin, this compacted structure needs to be opened up. The SWI/SNF complex helps to unwind the chromatin so that other proteins can have access to the DNA. Importantly, SWI/SNF also helps to bring DNA repair proteins to ultraviolet-induced DNA lesions.
Researchers at the University of Toledo believe that the SWI/SNF complex helps to trigger the repair of DNA damage caused by ultraviolet radiation. To determine how SWI/SNF does this, we altered the amount of SWI/SNF complex within melanocytes and then measured how much DNA damage was not repaired after exposure to ultraviolet radiation.
We discovered that decreased amounts of SWI/SNF in the cells led to more DNA damage that was not repaired after ultraviolet radiation. This indicates that the presence of SWI/SNF is necessary for efficient DNA repair in melanocytes after exposure to ultraviolet radiation.
When DNA damage takes place, an army of DNA repair proteins gathers at the site to correct the damage. This conglomeration of DNA repair proteins converging onto a damaged site is called repair foci. The number of repair foci is an accurate indication of the number of repairs occurring within the DNA. We discovered that, in the presence of normal amounts of SWI/SNF, the number of DNA repair foci was higher as compared to cells with reduced amounts of SWI/SNF.
SWI/SNF is actually a complex of many different proteins. Currently we are working to determine which of the SWI/SNF proteins are indispensable for repair of DNA lesions caused by ultraviolet radiation.
Our ultimate goal is to unravel the novel molecular mechanisms by which the SWI/SNF complex promotes DNA repair in melanocytes This information will provide more knowledge for therapeutic interventions to protect melanoma-susceptible people.
Shweta Aras is a PhD graduate student in the cancer biology track at the University of Toledo college of medicine and life sciences biomedical science program, the former Medical College of Ohio. She is doing her research in the laboratory of Dr. Ivana de la Serna. For more information, contact Shweta.Aras@rockets.utoledo.edu or go to utoledo.edu/med/grad/biomedical.
Read more at http://www.toledoblade.com/Medical/2015/02/02/Shining-a-light-on-the-darkness-of-melanoma.html#aIFZVklPbsvYZ9VY.99
The College of Graduate Studies announces availability of its 2015 Annual Fellowships, Scholarships and Awards! Complete descriptions, criteria and applications are located on the College of Graduate Studies website: http://www.utoledo.edu/graduate/scholarships/index-2.html
Current Graduate Students:
Robert R. Buell Memorial Achievement Award
Helen M. Fields Memorial Achievement Award
Robert N. Whiteford Memorial Scholarship
Prospective Graduate Students:
Graduate Opportunity Assistantship Award (GOAP)
McNair Scholars Award
(The above opportunities are primarily for prospective graduate students; however, in rare circumstances a first year graduate student may be considered.
All application deadlines are February 13, 2015.