Error Prone

Damaged chromosomes (blue arrows).  Source: Square87~commonswiki / Wikimedia Commons

The world is rough, especially on our genome.  Our DNA is regularly bombarded by sunlight, radiation, smoke and soot in the air [1].  Even our own natural metabolism creates chemical by-products that can damage DNA [2].  This damage occurs anywhere from 10,000 to 1,000,000 times per cell per day – a rate that should leave us squishy, mutated blobs.

Luckily, we have repair genes regularly fixing every nick in our genome.  One such repair gene is this week’s gene of interest: xeroderma pigmentosum, complementation group A or XPA.

Antioxidants have worked their way into every fiber of the health food market.  Anti-aging, cancer-fighting superfruit supplements.  Ads claim these products protect against free-radicals – villains robbing us of our health and youth [3].  But when put to the test, few antioxidant-rich foods can live up to marketing claims.  Basically, a healthy diet has all the antioxidants we need [4].

But there’s a bit of truth to the hype.  Free-radicals are destructive.  They’re natural by-products of our metabolism that regularly damage DNA through harmful chemical reactions.  For example, one by-product, reactive oxygen species (ROS), can react to convert the DNA nucleotide guanine into 8-oxoguanine [5].

The extra oxygen on the 8-oxoguanine isn’t a huge problem on its own, but when the cell copies its DNA, 8-oxoguanine can accidentally pair with adenine.  The code in DNA works under a very simple premise: A is paired with T, and C with G.  Therefore, if 8-oxoguanine is mispaired with adenine (G with A), that chemical reaction has effectively rewritten a small part of the genome [6].

This problem is as old as DNA – these types of chemical reactions have always eroded the code.  Nearly all life on earth has a way of fixing these errors quickly before they get out of hand.  One method is nucleotide excision repair (NER), and it requires XPA.

Nucleotide Excision Repair (NER)

First, DNA is scanned for errors.  When an 8-oxoguanine base is detected, several proteins, including XPA, form a complex at the site of the error.  The protein complex unwinds the double helix and cuts the DNA several base pairs away from the 8-oxoguanine base.  Once the chunk with the error is removed, a new protein complex rewrites the missing piece of DNA [7].

Good as new!  For about 9 seconds until another error forms somewhere else.

XPA is named after xeroderma pigmentosum (XP), a disorder caused by mutations in NER genes.  Cells have other repair mechanisms besides NER, but losing a gene like XPA means no NER and errors pile up quickly, especially in the sun.  In an earlier post, I mentioned sunburns are actually skin cells killing themselves in the face of overwhelming DNA errors.  People with XP sunburn in minutes – errors build up that quickly without NER.  They are also 10,000 times more vulnerable to skin cancer [8].  It’s the loss of NER in this disorder that reveals the daily attack on our DNA.   Without it, people with XP have to live their lives in the dark, protecting their genome from the harsh rays of the sun.

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References
[1] Lodish, H.; Berk, A.; Matsudaira, P.; Kaiser, CA.; Krieger, M.; Scott, M.P.; Zipursky, S.L.; Darnell, J. (2004). Molecular Biology of the Cell. New York, NY: WH Freeman. pp. 963. ISBN-10: 0-7167-3136-3.
[2] De Bont, R.; van Larebeke, N. (2004) “Endogenous DNA damage in humans: a review of quantitative data”. Mutagenesis 19 (3): 169-185. Review. PMID 15123782
[3] “POM-boozled: Do health drinks live up to their labels?”. CNN Health. 27 October 2010.
[4] “The Truth about Antioxidants”. Time. 6 August 2013.
[5] Kanvah, S.; et al. (2010). “Oxidation of DNA: Damage to Nucleobases”. Acc. Chem. Res. 43 (2): 280–287. PMID 19938827
[6] Cheng, K.C.; Cahill, D.S.; Kasai, H.; Nishimura, S.; Loeb, L.A. (1992). “8-Hydroxyguanine, an abundant form of oxidative DNA damage, causes G→T and C→A substitutions”. J Biol Chem. 267 (1): 166–72. PMID 1730583
[7] Le May, N.; Egly, J.M.; Coin, F. (2010). “True lies: the double life of the nucleotide excision repair factors in transcription and DNA repair”. J Nucleic Acids. 616342 PMID 20725631.
[8] “For Children with XP Gene, Sunlight Can Kill”. Everyday Health. 17 October 2012.