a nuclear localization signal, which results in the generation of c-Drosha. This variant has been shown to localize to the cell cytoplasm rather than the nucleus, but the effects on pri-miRNA processing are yet unclear. Both Drosha and Dicer also participate in the DNA damage response. Certain miRNAs have been found to deviate from conventional biogenesis pathways and do not necessarily require Drosha or Dicer, which is because they do not require the processing of pri-miRNA to pre-miRNA. Drosha-independent miRNAs derive from mirtrons, which are genes that encode for miRNAs in their introns and make use of splicing to bypass Drosha cleavage. Simtrons are mirtron-like, splicing-independent, and do require Drosha mediated cleavage, although they do not require most proteins in the canonical pathway such as DGCR8 or Dicer. Clinical significance Drosha and other miRNA processing enzymes may be important in cancer prognosis. Both Drosha and Dicer can function as master regulators of miRNA processing and have been observed to be down-regulated in some types of breast cancer. The alternative splicing patterns of Drosha in The Cancer Genome Atlas have also indicated that c-drosha appears to be enriched in various types of breast cancer, colon cancer, and esophageal cancer. However, the exact nature of the association between microRNA processing and tumorigenesis is unclear, but its function can be effectively examined by siRNA knockdown based on an independent validation. Drosha and other miRNA processing enzymes may also be important in HIV-1 replication. miRNAs contribute to the innate antiviral defense. This can be shown by the knockdown of two important miRNA processing proteins, Drosha and Dicer, which leads to a significant enhancement of viral replication in PBMCs from HIV-1-infected patients. Thus, Drosha, in conjunction with Dicer, seem to have a role in controlling HIV-1 replication. References Further reading External links Ribonucleases MicroRNA RNA interference RNA-binding proteins