PKA-Mediated Phosphorylation of ATR Promotes Recruitment of XPA to UV-Induced DNA Damage

What is it about?

The melanocortin 1 receptor (MC1R) is an important melanoma risk determinant. Expressed on the surface of melanocytes, it controls many aspects of how melanocytes respond to UV radiation. Since UV mutations are very common in melanoma, we know that how melanocytes cope with UV damage is critical to determining whether they will turn into melanoma. This study identifies how the MC1R signaling pathway intersects with DNA repair, the molecular pathway that fixes UV damage to a cell's DNA before that damage can cause a permanent (and potentially cancer-causing) mutation. We found that stimulating cells through the MC1R caused an enzyme called "protein kinase A" (PKA) to attach a phosphate group to an important cell damage response protein called ATR. Normally, when ATR gets activated, it stops a cell from dividing, but when PKA phosphorylates ATR, this does not happen. Rather, ATR physically binds a DNA repair protein called XPA and together they go to sites of UV damage in DNA. This leads to faster and more efficient repair of the damage and reduces mutations caused by UV.

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Why is it important?

This work is important because millions of people have inherited MC1R genes that encode MC1R proteins that don't work properly. These people, who tend to be fair-skinned and sun-sensitive, are at higher risk of melanoma. Our work explains why these individuals might get more melanoma (because they can't fix UV damage as well). More importantly, our studies suggest that sub-optimal DNA repair caused by poor MC1R function may be pharmacologically rescued by drugs that mimic MC1R signaling, offering the hope that DNA repair can be improved in MC1R-defective people and result in less melanoma.

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