Formaldehyde is able to form crosslinks between proteins and proteins and proteins and nucleic acids (DNA and RNA). This makes it useful for things like capturing nucleic-acid binding proteins where they’re bound in order to figure out where they’re bound (methods such as CHIP-seq), stabilizing complexes for structural studies (e.g. cryo-EM, crystallography), or fixing tissues (freezing things in place so you can stain them and stuff). But how does formaldehyde actually do it? Like, what’s the mechanism? It doesn’t look like it should be able to do much of anything…



Sorry I don’t have text for today, but here are some good papers if you want to learn more: 

Hoffman EA, Frey BL, Smith LM, Auble DT. Formaldehyde crosslinking: a tool for the study of chromatin complexes. J Biol Chem. 2015 Oct 30;290(44):26404-11. doi: 10.1074/jbc.R115.651679. Epub 2015 Sep 9. PMID: 26354429; PMCID: PMC4646298. https://doi.org/10.1074/jbc.R115.651679 

Kennedy-Darling J, Smith LM. Measuring the formaldehyde Protein-DNA cross-link reversal rate. Anal Chem. 2014 Jun 17;86(12):5678-81. doi: 10.1021/ac501354y. Epub 2014 Jun 3. PMID: 24848408; PMCID: PMC4063333. https://doi.org/10.1021/ac501354y

Kun Lu, Wenjie Ye, Li Zhou, Leonard B. Collins, Xian Chen, Avram Gold, Louise M Ball, and James A. Swenberg. Structural Characterization of Formaldehyde-Induced Cross-Links Between Amino Acids and Deoxynucleosides and Their Oligomers. Journal of the American Chemical Society 2010 132 (10), 3388-3399 DOI: 10.1021/ja908282f https://pubs.acs.org/doi/10.1021/ja908282f 

Hafner, M., Katsantoni, M., Köster, T. et al. CLIP and complementary methods. Nat Rev Methods Primers 1, 20 (2021). https://doi.org/10.1038/s43586-021-00018-1 

Park, P. ChIP–seq: advantages and challenges of a maturing technology. Nat Rev Genet 10, 669–680 (2009). https://doi.org/10.1038/nrg2641 

Lee FCY, Ule J. Advances in CLIP Technologies for Studies of Protein-RNA Interactions. Mol Cell. 2018 Feb 1;69(3):354-369. doi: 10.1016/j.molcel.2018.01.005. PMID: 29395060. https://www.sciencedirect.com/science/article/pii/S1097276518300054?via%3Dihub 

Burgos-Barragan, G., Wit, N., Meiser, J. et al. Mammals divert endogenous genotoxic formaldehyde into one-carbon metabolismNature 548, 549–554 (2017). https://doi.org/10.1038/nature23481 

Liu, X., Locasale, J. A toxin that fuels metabolism. Nature 548, 533–534 (2017). https://doi.org/10.1038/nature23541 

more on nucleophiles & electrophiles: http://bit.ly/nucleophilefiles 

more about protein-protein crosslinking: blog: https://bit.ly/crosslinkingoverview ; YouTube: https://youtu.be/K9Vz3KPVzFU


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