PMS2 has both pro-mutagenic and anti-mutagenic effects on repeat instability in the Repeat Expansion Diseases.

Expansion of a disease-specific tandem repeat is responsible for >45 Repeat Expansion Diseases (REDs). The mismatch repair protein PMS2 is a modifier of somatic expansion and disease severity in Huntington's disease (HD), a RED resulting from a CAG-repeat expansion. However, PMS2 shows different effects in different RED models, protecting against expansion in some and promoting it in others. To better understand this difference, we carried out a systematic study of the loss of PMS2 in mouse models of HD and the fragile X-related disorders (FXDs), a group of REDs resulting from a CGG-repeat expansion. In both models, loss of one Pms2 allele resulted in more expansions, while loss of both alleles resulted in more expansion in some organs but less in others. Thus, rather than reflecting different expansion mechanisms in different diseases, the previously reported differences in different model systems likely reflects the ability of PMS2 to promote expansion in some cellular contexts and to protect against it in others. In mouse embryonic stem cells containing both sets of repeats where PMS2 was expressed under the control of a doxycycline (DOX)-inducible promoter, low DOX concentrations produced a dose-dependent increase in expansions of both repeats, an effect that was dependent on the PMS2 nuclease domain, while higher DOX levels resulted in a decrease in expansions. Our findings have implications both for the mechanism of expansion and for therapeutic approaches to treat these diseases by reducing somatic expansion.