MBT domain proteins in development and disease

Abstract

The Malignant Brain Tumor (MBT) domain is a “chromatin reader”, a protein module that binds to post-translational modifications on histone tails that are thought to affect a variety of chromatin processes, including transcription. More specifically, MBT domains recognize mono- and di-methylated lysines at a number of different positions on histone H3 and H4 tails. Three Drosophila proteins, SCM, L(3)MBT and SFMBT contain multiple adjacent MBT repeats and have critical roles in development, maintenance of cell identity, and tumor suppression. Although they function in different pathways, these proteins all localize to chromatin in vivo and repress transcription by a currently unknown molecular mechanism that requires the MBT domains. The human genome contains several homologues of these MBT proteins, some of which have been linked to important gene regulatory pathways, such as E2F/Rb- and Polycomb-mediated repression, and to the insurgence of certain neurological tumors. Here, we review the genetics, biochemistry, and cell biology of MBT proteins and their role in development and disease.

USP7 Cooperates with SCML2 To Regulate the Activity of PRC1

“…Mice harboring a strong hypomorphic mutation of SCMH1 show homeotic transformations and defective spermatogenesis (8), and SCMH1 cooperates with PRC1 in the ubiquitination of geminin (9). The MBT repeats of SCML2 have been shown to bind to monomethylated lysines in histones (10,11), and we have recently shown that two different isoforms of SCML2 exhibit distinct functions in the regulation of the activation of CDK2/CYCE complexes and in gene repression by PRC1 (12,13).…”

Chromatin regulation: How complex does it get?

“…26,27 During evolution the MBT domain protein family has expanded to include 9 members in humans. 28 In accordance with the l(3)mbt phenotype in Drosophila several human MBT domain proteins (L3MBTL1, L3MBTL2, L3MBTL3, L3MBTL4, and SCML2) have been implicated in tumorigenesis. [28][29][30][31][32][33] In addition to MBT modules, these proteins often contain zinc fingers and Scm, Ph and MBT homology (SPM) domains.…”

Implicating SCF Complexes in Organogenesis in Caenorhabditis elegans

“…Notably, many class B SynMuv genes are conserved in mammals and function within several structurally related transcriptional repressor complexes (Fay and Yochem 2007;van den Heuvel and Dyson 2008). LIN-61 contains four malignant brain tumor (MBT) repeats, which bind to modified histones and are found in transcriptional repressors including the Polycomb-group proteins (Harrison et al 2007;Bonasio et al 2010). LIN-61 binds to histone H3 when this protein is di-or trimethylated on lysine 9 (Koester-Eiserfunke and Fischle 2011).…”