Parp3 promotes long-range end joining in murine cells

Significance Chromosomal rearrangements are early and essential events in the formation of many tumors. Two distinct end-joining pathways, classic and alternative nonhomologous end joining, can mediate rearrangement formation. Previous studies have shown that genetic factors mediating rearrangements differ significantly between mouse and human cells. Here we show that poly(ADP)ribose polymerase 3 (Parp3) uniquely promotes chromosomal rearrangements in both species. Using next-generation sequencing of rearrangement junctions, we investigated the mechanistic contribution of Parp3 and a closely related enzyme, Parp1, that is also known to promote rearrangements in murine cells. We find differences in the phenotypes of rearrangements in cells lacking Parp3, Parp1, or both, suggesting that these enzymes promote rearrangements through distinct mechanisms and providing insight into this essential mechanism of tumorigenesis. Chromosomal rearrangements, including translocations, are early and essential events in the formation of many tumors. Previous studies that defined the genetic requirements for rearrangement formation have identified differences between murine and human cells, most notably in the role of classic and alternative nonhomologous end-joining (NHEJ) factors. We reported that poly(ADP)ribose polymerase 3 (PARP3) promotes chromosomal rearrangements induced by endonucleases in multiple human cell types. We show here that in contrast to classic (c-NHEJ) factors, Parp3 also promotes rearrangements in murine cells, including translocations in murine embryonic stem cells (mESCs), class–switch recombination in primary B cells, and inversions in tail fibroblasts that generate Eml4–Alk fusions. In mESCs, Parp3-deficient cells had shorter deletion lengths at translocation junctions. This was corroborated using next-generation sequencing of Eml4–Alk junctions in tail fibroblasts and is consistent with a role for Parp3 in promoting the processing of DNA double-strand breaks. We confirmed a previous report that Parp1 also promotes rearrangement formation. In contrast with Parp3, rearrangement junctions in the absence of Parp1 had longer deletion lengths, suggesting that Parp1 may suppress double-strand break processing. Together, these data indicate that Parp3 and Parp1 promote rearrangements with distinct phenotypes.

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