TY - JOUR
T1 - DNA Packaging and Polycation Length Determine DNA Susceptibility to Free Radical Damage in Condensed DNA
AU - Oikeh, Ehigbai
AU - Ziebarth, Jesse
AU - Dinar, Md Abu Monsur
AU - Kirchhoff, Daniel
AU - Aronova, Anastasiia
AU - Dziubla, Thomas D.
AU - Wang, Yongmei
AU - DeRouchey, Jason E.
N1 - Publisher Copyright:
© 2024 American Chemical Society.
PY - 2024/4/11
Y1 - 2024/4/11
N2 - In nature, DNA exists primarily in a highly compacted form. The compaction of DNA in vivo is mediated by cationic proteins: histones in somatic nuclei and protamines in sperm chromatin. The extreme, nearly crystalline packaging of DNA by protamines in spermatozoa is thought to be essential for both efficient genetic delivery as well as DNA protection against damage by mutagens and oxidative species. The protective role of protamines is required in sperm, as they are sensitive to ROS damage due to the progressive loss of DNA repair mechanisms during maturation. The degree to which DNA packaging directly relates to DNA protection in the condensed state, however, is poorly understood. Here, we utilized different polycation condensing agents to achieve varying DNA packaging densities and quantify DNA damage by free radical oxidation within the condensates. Although we see that tighter DNA packaging generally leads to better protection, the length of the polycation also plays a significant role. Molecular dynamics simulations suggest that longer polyarginine chains offer increased protection by occupying more space on the DNA surface and forming more stable interactions. Taken together, our results suggest a complex interplay among polycation properties, DNA packaging density, and DNA protection against free radical damage within condensed states.
AB - In nature, DNA exists primarily in a highly compacted form. The compaction of DNA in vivo is mediated by cationic proteins: histones in somatic nuclei and protamines in sperm chromatin. The extreme, nearly crystalline packaging of DNA by protamines in spermatozoa is thought to be essential for both efficient genetic delivery as well as DNA protection against damage by mutagens and oxidative species. The protective role of protamines is required in sperm, as they are sensitive to ROS damage due to the progressive loss of DNA repair mechanisms during maturation. The degree to which DNA packaging directly relates to DNA protection in the condensed state, however, is poorly understood. Here, we utilized different polycation condensing agents to achieve varying DNA packaging densities and quantify DNA damage by free radical oxidation within the condensates. Although we see that tighter DNA packaging generally leads to better protection, the length of the polycation also plays a significant role. Molecular dynamics simulations suggest that longer polyarginine chains offer increased protection by occupying more space on the DNA surface and forming more stable interactions. Taken together, our results suggest a complex interplay among polycation properties, DNA packaging density, and DNA protection against free radical damage within condensed states.
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U2 - 10.1021/acs.jpcb.3c06116
DO - 10.1021/acs.jpcb.3c06116
M3 - Article
C2 - 38557033
AN - SCOPUS:85189532150
SN - 1520-6106
VL - 128
SP - 3329
EP - 3339
JO - Journal of Physical Chemistry B
JF - Journal of Physical Chemistry B
IS - 14
ER -