Figure 9.

Simplified overview of the cell cycle–related pathways impaired in anauxetic dysplasia and CHH. Right, The hereby affected RMRP gene encodes the untranslated RNA subunit of the ribonucleoprotein endoribonuclease, RNase MRP, which is essential for cell growth and division in yeast and, as our data suggest, also in humans. One function of the RNase MRP complex is the processing of the precursor of 5.8S rRNA, which is a subunit of the 60S ribosomal particle. Therefore, severe and moderate disruption (red flashes) of RNase MRP function in anauxetic dysplasia and CHH, respectively, impacts late-60S ribosomal assembly, resulting in a reduced capacity to synthesize proteins. As a secondary effect, cyclin A2, which promotes G1/S and G2/M phase transitions, is diminished, correlating with the magnitude of delay in the cell cycle. Left, The second function of RNase MRP complex in yeast and, apparently, in humans is the degradation of cyclin B2 mRNA, which is important for the exit of mitosis. In contrast to anauxetic dyplasia, the latter pathway is also impacted in CHH, as shown by increased cyclin B2 mRNA levels. Since cyclin B2 overexpression from different mechanisms contributes through alterations of the spindle checkpoint to the chromosomal instability observed in some cancers, our findings could also explain why only CHH, and not anauxetic dysplasia, is associated with proliferative bone marrow dysfunction and susceptibility to cancer.