title: MMSET is dynamically regulated during cell-cycle progression and promotes normal DNA replication.
abstract: The timely and precise duplication of cellular DNA is essential for maintaining genome integrity and is thus tightly-regulated. During mitosis and G1, the Origin Recognition Complex (ORC) binds to future replication origins, coordinating with multiple factors to load the minichromosome maintenance (MCM) complex onto future replication origins as part of the pre-replication complex (pre-RC). The pre-RC machinery, in turn, remains inactive until the subsequent S phase when it is required for replication fork formation, thereby initiating DNA replication. Multiple myeloma SET domain-containing protein (MMSET, a.k.a. WHSC1, NSD2) is a histone methyltransferase that is frequently overexpressed in aggressive cancers and is essential for normal human development. Several studies have suggested a role for MMSET in cell-cycle regulation; however, whether MMSET is itself regulated during cell-cycle progression has not been examined. In this study, we report that MMSET is degraded during S phase in a cullin-ring ligase 4-Cdt2 (CRL4(Cdt2)) and proteasome-dependent manner. Notably, we also report defects in DNA replication and a decreased association of pre-RC factors with chromatin in MMSET-depleted cells. Taken together, our results suggest a dynamic regulation of MMSET levels throughout the cell cycle, and further characterize the role of MMSET in DNA replication and cell-cycle progression.
authors.affiliation: a Mayo Graduate School, Biochemistry and Molecular Biology (BMB) Track, Mayo Clinic , Rochester , MN , USA.
authors.forename: Debra L
authors.initials: DL
authors.lastname: Evans
authors.affiliation: b Division of Oncology Research , Department of Oncology, Mayo Clinic , Rochester , MN , USA.|c School of life sciences, Southwest University , Chongqing , China.
authors.forename: Haoxing
authors.initials: H
authors.lastname: Zhang
authors.affiliation: d Mayo Graduate School, Immunology Track, Mayo Clinic , Rochester , MN , USA.
authors.forename: Hyoungjun
authors.initials: H
authors.lastname: Ham
authors.affiliation: b Division of Oncology Research , Department of Oncology, Mayo Clinic , Rochester , MN , USA.|e State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine , Beijing , China.
authors.forename: Huadong
authors.initials: H
authors.lastname: Pei
authors.affiliation: b Division of Oncology Research , Department of Oncology, Mayo Clinic , Rochester , MN , USA.
authors.forename: SeungBaek
authors.initials: S
authors.lastname: Lee
authors.affiliation: b Division of Oncology Research , Department of Oncology, Mayo Clinic , Rochester , MN , USA.
authors.forename: JungJin
authors.initials: J
authors.lastname: Kim
authors.affiliation: b Division of Oncology Research , Department of Oncology, Mayo Clinic , Rochester , MN , USA.|d Mayo Graduate School, Immunology Track, Mayo Clinic , Rochester , MN , USA.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Billadeau
authors.affiliation: b Division of Oncology Research , Department of Oncology, Mayo Clinic , Rochester , MN , USA.
authors.forename: Zhenkun
authors.initials: Z
authors.lastname: Lou
mesh_terms: D002453:Cell Cycle / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology; D004261:DNA Replication / Q000502:physiology*; D045325:HCT116 Cells; D006367:HeLa Cells; D011495:Histone-Lysine N-Methyltransferase / Q000502:physiology*; D006801:Humans; D012097:Repressor Proteins / Q000502:physiology*
chemical_list: D012097:Repressor Proteins; D011495:Histone-Lysine N-Methyltransferase; C419586:NSD2 protein, human
keywords: Cdt2; DNA replication; E3 ubiquitin ligase; MMSET; cell cycle; proliferating cell nuclear antigen (PCNA); ubiquitin