Affinity for DNA Contributes to NLS Independent Nuclear Localization of MeCP2

MeCP2 is a nuclear protein that is mutated in the severe neurological disorder Rett syndrome (RTT). The ability to target β-galactosidase to the nucleus was previously used to identify a conserved nuclear localization signal (NLS) in MeCP2 that interacts with the nuclear import factors KPNA3 and KPNA4. Here, we report that nuclear localization of MeCP2 does not depend on its NLS. Instead, our data reveal that an intact methyl-CpG binding domain (MBD) is sufficient for nuclear localization, suggesting that MeCP2 can be retained in the nucleus by its affinity for DNA. Consistent with these findings, we demonstrate that disease progression in a mouse model of RTT is unaffected by an inactivating mutation in the NLS of MeCP2. Taken together, our work reveals an unexpected redundancy between functional domains of MeCP2 in targeting this protein to the nucleus, potentially explaining why NLS-inactivating mutations are rarely associated with disease. [Display omitted] •Nuclear localization of MeCP2 does not require its NLS•DNA binding by MeCP2 contributes to its NLS-independent nuclear localization•MeCP2 NLS mutation does not affect pathology in a mouse model of Rett syndrome Lyst et al. report that nuclear localization of MeCP2 does not require its nuclear localization signal. Instead, this protein is efficiently partitioned in the nucleus via its affinity for DNA. Consistent with this finding, mutating the MeCP2 NLS does not affect pathology in a mouse model of Rett syndrome.