Genome Instability is Breathtaking

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1 Genome Instability is Breathtaking Effects of Alpha Radiation exposure on DNA at a molecular level and consequences to cell health Dr. Aaron Goodarzi A.Goodarzi@ucalgary.ca

2 Radiation what do you think of?

3 Radiation Exposure Radon gas inhalation accounts for most of our annual radiation exposure

4 Ionizing Radiation

5 Radiation Dosages Comic from: Radiation doses are commonly measured with three different units. The easiest way to conceptualize them is to think of Sir Isaac Newton under his apple tree. Becquerel (Bq) An absolute measure of radioactivity. Equivalent to 1 radioactive disintegration (particle emission) per second Gray (Gy) The dose of radiation absorbed by the object. Equivalent to 1 joule of energy per kilogram Sievert (Sv) The dose absorbed by a body which has an effect. Can be same as Gray.

6 Linear Energy Transfer Linear Energy Transfer (LET) is an important quality consideration for different types of radiation. LET = ionization events per unit length of a given ionization track Same dose = Image courtesy of: Low LET High LET

7 Radiation Dosages

8 Radiation and DNA damage All our DNA is found in our 2 copies (one from mom, one from dad) of 23 unique chromosomes.

9 DNA is packaged carefully DNA is wrapped around packaging proteins to form chromatin, keeping it generally stable and amenable for use by the cell

10 DNA Damage Figure adapted from:

11 DNA Double Strand Breaks

12 Radiation and DNA damage DNA damage is usually repaired by our cells correctly. However, errors are made... DNA damage = error = genetic mutation = cancer A = normal cell B = cancer cell

13 Life, Mutation or Death? Outcome depends on IR dose DNA DSBs 25 mgy IR = DSB/cell (low risk of cancer, +1% to lifetime risk) 250 mgy IR = 5-10 DSB/cell (significant increase in risk of cancer) 2,500 mgy IR = DSB/cell (radiation poisoning, cancer >95% sure) 25,000 mgy IR = DSB/cell (death is inevitable)

14 Radiation and Cancer When connecting radiation exposure to cancer, we stereotypically think of nuclear attack or disaster. Increased risk of solid cancer versus dose for atomic bomb survivors

15 Radiation and Cancer Following Chernobyl, thyroid cancer rates soared in children and young adults as radioactive iodine isotopes were absorbed by cows across Eastern Europe and concentrated into milk. The adult, mostly Ukrainian, clean-up workers ( liquidators ) from the army, plant staff and emergency services often went on to get leukemia. They generally received >100 msv exposures.

16 Radiation and Cancer Time will tell how cancer rates in Eastern Japan will change, following the 2011 Fukushima power plant meltdown.

17 Radon Exposure and Cancer In 2005, the WHO set up the International Radon Project, to outline risks and make recommendations.

18 Radon: a leading cause of lung cancer UN study concluded relative risk of lung cancer increases ~16% for every 100 Bq/m 3. WHO handbook on indoor Radon, Bq/m 3 = one hundred particles of alpha radiation emitted every second per cubic metre of air

19 Radon exposure in youth is serious Radon exposure during youth linearly increases risk of lung cancer. The younger you are at age of exposure, the greater is your chance of living long enough to get lung cancer. Chen, J. Canadian Lung Cancer relative Risk from Radon Exposure for Short Periods in Childhood Compared to a Lifetime. Int. J. Environ. Res. Public Health 2013, 10, e.g. exposure to 400 Bq/m 3 from ages 0-17 is same as a lifetime at 100 Bq/m 3

20 Radon = -particle radiation 234 Uranium For every atom of Rn 222 inhaled, four α-particles are emitted, three in the first week α α α 2.33x10 5 yrs 222 Radon α 3.8 days 218 Polonium 3.05 min 214 Polonium Remaining radioactive lead continues to emit alpha radiation for 22 years. α β β 1.5x10 4 sec 210 Lead α β β α 22.3 yrs β β Stable 206 Lead

21 -particles = High LET IR Low LINEAR ENERGY TRANSFER (LET) IR Resulting damage to DNA is more widely spaced, and is comparatively easier to repair High LINEAR ENERGY TRANSFER (LET) IR Resulting damage to DNA is clustered together, and is much more challenging to repair accurately.

22 -particles = clustered DNA damage The CLUSTERING of DNA damage can impact the accuracy of DNA repair substantially. Low LET IR Relatively straightforward rejoining During interphase, our chromosomes largely exist within independent territories, but do overlap to a degree.

23 % unrepaired DNA breaks DNA repair kinetics for low LET IR Gy 0.5 hr 2 hr 8 hr 24 hr 48 hr 72 hr >7 days Hours after irradiation

24 -particles = Clustered DNA damage The CLUSTERING of DNA damage can impact the accuracy of DNA repair substantially. Severe fragmentation and proximity of breaks from multiple chromosomes makes accurate re-joining difficult High LET IR

25 % unrepaired DNA breaks DNA repair kinetics for high LET IR Hours after irradiation >7 days

26 Clustered DNA damage Figure adapted from Moore S, Stanley FK, Goodarzi AA. The repair of DNA double strand breaks caused by high linear energy transfer irradiation - no simple task. DNA Repair : Review.

27 Influence of Genetics Your genetics plays a huge role in your likelihood of getting cancer following a trigger For breast/cervical cancer, mutation of BRCA1/BRCA2 are well known risk factors But what about radiation-induced lung cancer? GSTM1, GSTT1 Ruano-Ravina et al., 2014 (J. Thorac Oncol.) SIRT1 Leng et al., 2013 (Carcinogenesis) MGMT Pulling et al., 2003 (Cancer Research)????????????????????????????????????

28 Influence of Genetics The ATM gene is one of the more commonly mutated factors known to contribute to cancer and radio-sensitivity Basically, a lot more research is required to define the genetic risks of lung cancer following radon exposure. Riballo, E. et al. Molecular Cell 16, (2004)

29 ACKNOWLEDGEMENTS GOODARZI LAB Rami Abou-Zeinab, PhD Alex Anikin, BSc Karolin Klement, PhD Shaun Moore, BSc Dustin Pearson, MSc Carin Pihl, BSc Shilpa Salgia, MSc Fintan Stanley, BSc

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