Is Cryptochrome A Primary Sensor Of Extremely Low Frequency Magnetic Fields In Childhood Leukemia?

Extremely low frequency magnetic fields (ELF MF) are classified as possibly carcinogenic to humans, but the biophysical mechanisms of a causal relationship remain unclear. A cryptochrome-based radical pair mechanism (RPM) has been invoked as the primary MF sensor in animal magnetoreception to explain effects from MF strengths in the nT range. Model studies of the RPM in aprotic solution require cryogenic temperatures and MFs in the µT range to elicit marginal responses, implying that physiological responses evoked by radical pairs in biological milieu are unlikely. We explore ideas about how signals from transient radical pairs in cryptochrome might be transduced and amplified in mutagenic responses. The cryptochrome-based RPM involves blue light activation of the flavin adenine dinucleotide (FAD) cofactor followed by electron transfer (ET) from a conserved triad of tryptophan residues. However, intramolecular ET involving additional conserved aromatic residues in cryptochrome likely extends beyond the canonical triad. Further, ascorbate, which is present at millimolar concentrations in leukocytes, is likely to transfer an electron to the ultimate amino acid radical formed during one-electron reduction of FAD. The ascorbyl radical has been proposed as a potential radical pair partner in the RPM.The flavin semiquinone radical may be reoxidized to the resting state via ET to O2 to form O2•−. Increased levels of the ascorbyl radical and O2•− would contribute to oxidative stress pathways in the cell. Oxidative stress responses in cancer are thought to be mediated in part by the mitogen activated protein kinase (MAPK) signaling pathway. We have presented evidence for alteration of MAPK activation in response to ELF MF.Acknowledgement: This project has received funding from the European Unionu0027s Seventh Programme for research, technological development, and demonstration under grant agreement No. 282891.