The remodeling of Z-DNA in the mammalian germ line

We recently discovered a novel biological process, the scheduled remodeling of Z-DNA structures in the developing fetal mouse male germ cells [Nat. Cell Biol. 24, 1141-1153]. This process affects purine/pyrimidine dinucleotide repeat (PPR) rich sequences, which can form stable left-handed Z-DNA structures. The protein that carries out this function is identified as ZBTB43, member of a large family of ZBTB proteins. Z-DNA remodeling by ZBTB43 not only coincides with global remodeling of DNA methylation and chromatin events in the male germ line, but it also is a prerequisite for de novo DNA methylation. When ZBTB43 changes DNA structure from the left-handed zigzag shaped Z-DNA to the regular smooth right-handed B-DNA, it also generates a suitable substrate for the de novo DNA methyltransferase, DNMT3A. By instructing de novo DNA methylation at PPRs in prospermatogonia, ZBTB43 safeguards epigenomic integrity of the male gamete. PPRs are fragile sequences, sites of large deletions and rearrangements in mammalian cells, and this fragility is thought to be due to Z-DNA structure formation rather than the sequence itself. This idea is now supported by the in vivo finding that DNA double strand breaks accumulate in mutant prospermatogonia which lack ZBTB43-dependent Z-DNA remodeling. If unrepaired, double stranded DNA breaks can lead to germ line mutations. Therefore, by preventing such breaks ZBTB43 is critical for guarding genome stability between generations. Here, we discuss the significance and implications of these findings in more detail.