Cleavage enzymes include Angiogenin, Dicer, RNase Z and RNase P. In the cytoplasm, the pre-miRNA hairpin is cleaved by the RNase III enzyme Dicer. Decreased dicer mRNA levels correlate with advanced tumor stage. The Dicer enzyme catalyzes production of siRNAs from long dsRNAs and small hairpin RNAs. The double-stranded molecule is then cut into small double-stranded fragments by an enzyme called Dicer. Overall hairpin length and loop size influence the efficiency of Dicer processing. Certain Dicer enzymes may be responsible for loading the guide strand into RISC. It is theorized that the resulting siRNA transcript is then processed by Dicer. Mice with Dicer knocked out, lacking Dicer only in their RPE, exhibited similar symptoms. Dicer orthologs are present in many other organisms. A study showed that many patients that had cancer had decreased expression levels of Dicer. The pre-miRNA is processed by the protein DICER into a double stranded 22 nucleotide. The same study showed that lower Dicer expression correlated with lower patient survival length. Both Drosha and Dicer also participate in the DNA damage response. Dicer is also involved in DNA repair.