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How does formaldehyde cause protein-DNA crosslinking? I would guess it's because the strongly polar water molecule interacts strongly with polar residues on a protein-DNA complex, and adding a less polar solvent causes the DNA and protein to pull more tightly on each other than their pull on the solvent, but I haven't been able to find an answer online.

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aldehydes actually react with amines in protein and DNA to covalently attach the protein to the DNA in such experiments. check out slides 3+ – shigeta Feb 3 '13 at 5:55
up vote 2 down vote accepted

In this work they find that formaldehyde crosslinking happens by formation of a methylol adduct (due to nucleophilic attack by N or S in case of proteins) in protein which then attacks the DNA or vice-versa. The final crosslink is by a methylene bridge

Formaldehyde can react to amino groups in nucleotides and proteins and form a schiff's base, but i dont have a clue how this is involved in crosslinking

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