Abstract B81: Structural insights into the regulation and the recognition of histone marks by the SET domain of NSD1.
Authors: Luccio Eric di , Morishita Masayo 
Published: June 2012

Background: The nuclear receptor binding SET domain (NSD) protein is a family of three histone-lysine N-methyltransferase (HMTase), NSD1, NSD2/MMSET/WHSC1, and NSD3/WHSC1L1 that are critical in maintaining the chromatin integrity. NSD1 methylates H3K36 and H4K20 and is associated with acute myeloid leukemia, multiple myeloma, and lung cancer. The NSD1-NUP98 translocation plays a significant role in childhood acute myeloid leukemia with the NUP98-NSD1 fusion protein being an active H3K36 methylase. NSD1 is amplified in multiple myeloma, lung cancer, neuroblastomas and glioblastomas. NSD2 methylates H3K4 and H4K20 and is linked to prostate cancer and multiple myeloma. Increased NSD2 activity was reported in the tumor proliferation in glioblastoma multiform. Over expression of NSD2 in myeloma cells leads to aberrantly high global levels of H3K36 di-methylation, accompanied by a decrease in H3K27 methylation. In myeloma cells, NSD2 contributes to disrupt the chromatin structure and function contributing to the cellular transformation. In addition, NSD2 is found over expressed in fifteen different cancers and is associated with tumor aggressiveness or prognosis in most types of cancers. NSD3 methylates H3K36 and is associated with both lung and breast cancer along with the acute myeloid leukemia. Furthermore, the amplification of either NSD1 or NSD2 triggers the cellular transformation, initiating carcinogenesis events NSD3 is found amplified in breast cancer cell lines and primary breast carcinomas. Reducing NSDs activity through specific and selective lysine-HMTase inhibitors appears promising to help suppressing cancer growth. However, little is known about the NSD pathways and our understanding of the histone Lysine-HMTase mechanism is partial. Analysis of the recent crystal-structure of the peptide-less SET domain of NSD1 revealed that in absence of ligand, the histone-binding site is occluded preventing any access to the catalytic groove. Therefore, we hypothesized that the SET domain of NSD1 has specific mechanisms to recognize histone marks and to grant access to the histone-binding site, unlike other HMTase.

Methods: We used computational methods to investigate the structural mechanisms happening in the SET domain during the binding of the H4-histone tail, exploiting the recent crystal structure of the peptide-less SET domain of NSD1.

Results: Our finding exposes a key regulatory and a recognition mechanism driven by the flexibility of a loop at the interface of the SET and postSET region who rotates ∼45° and translated 7 angstroms opening the SET domain for the binding of the peptide ligand. This regulatory loop acts as a seat belt for the ligand and contributes to the discrimination and the substrate specificity. HMTase inhibitors are scare, but their design relies on exploiting dissimilarities in the histone-tail binding pocket. Our data bring significant insight into the design of specific and selective NSD-HMTase inhibitors.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B81.