Table 2.

Summary of impacts of internal and external factors on Z-DNA formation

Group	Factor	Condition	Potential mechanism	Refs
Internal factors	DNA sequence	Alternating purine-pyrimidine motifs [e.g., d(GC/CG), d(TG), d(GGGC), d(TA) ], d(GC/CG) > d(TG) /d(GGGC) > d(TA)	Higher propensity for Z-DNA formation (descending order for listed motifs)	[42,47,48]
	Base modifications	High GC content, mismatched base pairs (e.g., G·T, G·Br5U, 5FU·G)	Favors Z-DNA conformation via structural destabilization	[49,50]
		Cytosine modifications (e.g., 5mC, C5 halogenation/bromination)	Reduces activation energy, destabilizes B-DNA, promotes B-Z transition	[3,52,53]
		Guanine modifications (e.g., C8 methylation/bromination, 8-oxodG, Ac-4 HAQO)	Distorts Watson-Crick pairing, stabilizes Z-DNA	[53,54]
	ZBPs	ZBPs with Zα domains (e.g., ADAR1, ZBP1, E3L, PKZ, ORF112, RBP7910, HOP2, DsvD, D2PEW5, feoC, pefI, RPA2, CDC53, CUL1 ANC2, APC2, Rpc34, PBP2, Reut_B4095)	Stabilize Z-DNA via specific binding to left-handed helix	[64,65]
	Processive enzymes	Polymerases and helicases	Inducing DNA under-rotation through mechanical stress and triggering B-Z conformational transition	[40]
External factors	Cations	Multivalent ions (Ru4+, Rh3+, Co3+ {[Co(NH3)6]Cl3}, Co2+ {CoCl2}, Mn2+, Mg2+, Ba2+, Ca2+); high NaCl (4 M) or LiCl (3.8 M)	Shielding of DNA backbone, reduces electrostatic repulsion	[3,41,56]
	Polyamines/osmolytes	Spermidine, spermine	Neutralize charges, alter water potential, stabilize Z-DNA	[3]
	Osmolytes	Alcohols (ethanol), polyols (sucrose)	Altering the chemical potentials of water and osmotic stress	[58,59]
	Mechanical stress	Negative supercoiling/torsional stress	Promotes the B-to-Z DNA transition by relieving torsional stress through Z-DNA’s left-handed structure	[21,60,61]
		DNA bending	Changing the spiral trajectory to reduce energy barriers	[62,63]
	Crowding agents	PEG200, ethylene glycol	Dehydration and crowding effects promote B-Z transition	[3,41,56]
	Compounds	Actinomycin D	By synergistically binding Z-DNA and inducing its local reversal to the right-handed B-type conformation	[46]
		Actinomycin	Dependent on positive charge to bind Z-DNA under low-salt/metal ion conditions and partially reverses its structure	[46]