hDOT1L Links Histone Methylation to Leukemogenesis

Okada, Yuki; Qin, Feng; Lin, Yuan; Jiang, Qi; Li, Yaqiang; Coffield, Vernon M.; Su, Lishan; Xu, Guoliang; Zhang, Yi

doi:10.1016/j.cell.2005.05.021

Cited by 124 publications

(196 citation statements)

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“…Histone H3 lysine 79 methylase, hDOT1L, interacts with the MLL-AF10 fusion protein, and results in leukemic transformation [125]. Further, hDOT1L has also been shown to cause leukemia through its interaction with MLL in a methylase activity-dependent manner [125]. In fact, upregulation of a number of leukaemiaassociated genes (e. g., Hoxa9) with hypermethylation of lysine 79 on histone H3 was observed in MLLhDOT1L and MLL-AF10 transformed cells.…”

Section: Mll4mentioning

confidence: 96%

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Histone methylation and ubiquitination with their cross-talk and roles in gene expression and stability

Shukla

Chaurasia

Bhaumik

2008

Cell. Mol. Life Sci.

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Methylation of lysine residues of histones is associated with functionally distinct regions of chromatin, and, therefore, is an important epigenetic mark. Over the past few years, several enzymes that catalyze this covalent modification on different lysine residues of histones have been discovered. Intriguingly, histone lysine methylation has also been shown to be cross-regulated by histone ubiquitination or the enzymes that catalyze this modification. These covalent modifications and their cross-talks play important roles in regulation of gene expression, heterochromatin formation, genome stability, and cancer. Thus, there has been a very rapid progress within past several years towards elucidating the molecular basis of histone lysine methylation and ubiquitination, and their aberrations in human diseases. Here, we discuss these covalent modifications with their cross-regulation and roles in controlling gene expression and stability.

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Section: Mll4mentioning

confidence: 96%

“…For example, the MLL-AF10 fusion protein is involved in acute myeloid leukemia. Histone H3 lysine 79 methylase, hDOT1L, interacts with the MLL-AF10 fusion protein, and results in leukemic transformation [125]. Further, hDOT1L has also been shown to cause leukemia through its interaction with MLL in a methylase activity-dependent manner [125].…”

Section: Mll4mentioning

confidence: 98%

Histone methylation and ubiquitination with their cross-talk and roles in gene expression and stability

Shukla

Chaurasia

Bhaumik

2008

Cell. Mol. Life Sci.

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“…barrier-toautointegration factor 47, BAF47) protein [89]. SS18 might also interact through AF10 with the histone methyltransferase DOT1L (disruptor of telomeric silencing 1-like) [90].…”

Section: Ss18 Domains Snh and Qpgy Possess Disordered Motifs And Formmentioning

confidence: 99%

Synovial sarcoma is a gateway to the role of chromatin remodeling in cancer

Zöllner

Toretsky

2015

Cancer Metastasis Rev

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Patients afflicted with synovial sarcoma share the fate of other translocation positive sarcomas; the driver mutation for this cancer is known, yet no means to target the fusion protein SS18-SSX directly exist. Current chemotherapeutic regimens are minimally beneficial, particularly in patients with metastatic disease. SS18-SSX putatively promotes its oncogenic activity through protein-protein interactions that alter genetic programs through chromatin remodeling. This review discusses the functional protein network of SS18-SSX, both wild-type and fusion protein, considers its intrinsically disordered nature, and provides insights into potential therapeutic strategies. A comprehensive overview of the clinical characteristics reveals the need for newly targeted therapeutics based upon oncogenic transformation by the fusion protein SS18-SSX. The wild-type, non-fused proteins SS18 and SSX are presented including their molecular structure and biological function with regard to protein-protein interactions. The interactions of the wild-type proteins inform the oncogenic changes of the fusion protein. The SS18-SSX fusion protein and its protein interactions are described and evaluated for their biological consequences that lead to oncogenesis. This review illustrates the key protein interactions of SS18-SSX that may qualify as primary targets for small molecule-based disruption leading to the development of SS18-SSX-specific drugs. These novel targeted therapeutics may provide a specificity that ultimately improves survival while reducing morbidity of patients with synovial sarcoma.

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“…H3-K79 methylation is dependent on H2B ubiquitination, but the upstream pathway related to H4-K20 methylation remains elusive. H2B ubiquitination and H3 methylation are indispensable in mammalian development, genome integrity and human carcinogenesis [98,99].…”

Section: Role Of Ubiquitination In Homologous Recombination Repairmentioning

confidence: 99%

Role of ubiquitination in meiotic recombination repair

2010

Sci. China Life Sci.

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Programmed and unprogrammed double-strand breaks (DSBs) often arise from such physiological requirements as meiotic recombination, and exogenous insults, such as ionizing radiation (IR). Due to deleterious impacts on genome stability, DSBs must be appropriately processed and repaired in a regulatory manner. Recent investigations have indicated that ubiquitination is a critical factor in DNA damage response and meiotic recombination repair. This review summarizes the effects of proteins and complexes associated with ubiquitination with regard to homologous recombination (HR)-dependent DSB repair.

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hDOT1L Links Histone Methylation to Leukemogenesis

Cited by 124 publications

References 0 publications

Histone methylation and ubiquitination with their cross-talk and roles in gene expression and stability

Histone methylation and ubiquitination with their cross-talk and roles in gene expression and stability

Synovial sarcoma is a gateway to the role of chromatin remodeling in cancer

Role of ubiquitination in meiotic recombination repair

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