Citations

Significance We show that DNA double-strand breaks (DSBs) can be repaired by insertion of 50- to 1,000-bp sequences termed “templated-sequence insertions” (TSIs) derived from distant regions of the genome. Additional experiments indicate that the source of template for repair was primarily nuclear RNA. This mode of DNA-DSB repair by insertion is not restricted to experimentally produced breaks but also occurs at the site of spontaneous DNA DSBs in human cells. These TSIs are polymorphic in the human genome, suggesting that some TSIs occur in germ cells or embryos. Recognition of these TSIs is important in interpreting structural variations in short-read sequencing studies and provides additional polymorphic markers for population and evolution studies. This error-prone form of DNA repair may play a role in genetic diseases.

Prostate cancer is the second leading cause of cancer death among United States men. However, disease aggressiveness is varied, with low-grade disease often being indolent and high-grade cancer accounting for the greatest density of deaths. Outcomes are also disparate among men with high-grade prostate cancer, with upwards of 65% having disease recurrence even after primary treatment. Identification of men at risk for recurrence and elucidation of the molecular processes that drive their disease is paramount, as these men are the most likely to benefit from multimodal therapy. We previously showed that androgen-induced expression profiles in prostate development are reactivated in aggressive prostate cancers. Herein, we report the down-regulation of one such gene, Sparcl1 , a secreted protein, acidic and rich in cysteine (SPARC) family matricellular protein, during invasive phases of prostate development and regeneration. We further demonstrate a parallel process in prostate cancer, with decreased expression of SPARCL1 in high-grade/metastatic prostate cancer. Mechanistically, we demonstrate that SPARCL1 loss increases the migratory and invasive properties of prostate cancer cells through Ras homolog gene family, member C (RHOC), a known mediator of metastatic progression. By using models incorporating clinicopathologic parameters to predict prostate cancer recurrence after treatment, we show that SPARCL1 loss is a significant, independent prognostic marker of disease progression. Thus, SPARCL1 is a potent regulator of cell migration/invasion and its loss is independently associated with prostate cancer recurrence.