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Protamine folds DNA into flowers and loop stacks

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BIOPHYSICAL JOURNAL
卷 122, 期 21, 页码 4288-4302

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CELL PRESS
DOI: 10.1016/j.bpj.2023.10.003

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DNA in sperm undergoes extreme compaction and reorganization by protamine proteins, forming a series of toroidal structures. Protamine binds and bends DNA into loops and flowers, which then collapse into loop stacks. This mechanism allows protamine to quickly fold the DNA.
DNA in sperm undergoes an extreme compaction to almost crystalline packing levels. To produce this dense packing, DNA is dramatically reorganized in minutes by protamine proteins. Protamines are positively charged proteins that coat negatively charged DNA and fold it into a series of toroids. The exact mechanism for forming these -50-kbp toroids is un-known. Our goal is to study toroid formation by starting at the bottomwith folding of short lengths of DNA that form loops and working upto more folded structures that occur on longer length scales. We previously measured folding of 200-300 bp of DNA into a loop. Here, we look at folding of intermediate DNA lengths (L 1/4 639-3003 bp) that are 2-10 loops long. We observe two folded structures besides loops that we hypothesize are early intermediates in the toroid formation pathway. At low prot-amine concentrations (-0.2 mM), we see that the DNA folds into flowers (structures with multiple loops that are positioned so they look like the petals of a flower). Folding at these concentrations condenses the DNA to 25% of its original length, takes seconds, and is made up of many small bending steps. At higher protamine concentrations (R2 mM), we observe a second folded structure-the loop stack-where loops are stacked vertically one on top of another. These results lead us to propose a two-step process for folding at this length scale: 1) protamine binds to DNA, bending it into loops and flowers, and 2) flowers collapse into loop stacks. These results highlight how protamine uses a bind-and-bend mechanism to rapidly fold DNA, which may be why protamine can fold the entire sperm genome in minutes.SIGNIFICANCE Folding by protamine is important in both in vivo nuclear organization in sperm and in vitro condensation by condensing agents. Condensing agents are a class of positively charged molecules that condense DNA into toroids. Although DNA folding into a toroid was discovered over five decades ago, the exact physical mechanism for toroid formation is unknown. Here we identify two folded structures-flowers and loop stacks-that we hypothesize are early intermediates in the toroid formation pathway. In addition, we find that protamine bends DNA all along its length, creating rapid folding to 25% of the original length in seconds. This suggests a physical mechanism for how protamine can perform the substantial genome reorganization we see in sperm in minutes.

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