SETD1A Methyltransferase Is Physically and Functionally Linked to the DNA Damage Repair Protein RAD18

Alsulami, Manal; Munawar, Nayla; Dillon, Eugene; Oliviero, Giorgio; Wynne, Kieran; Alsolami, Mona; Moss, Catherine; Gaora, Peadar Ó; O’Meara, Fergal; Cotter, David; Cagney, Gerard

doi:10.1074/mcp.ra119.001518

Cited by 20 publications

(20 citation statements)

References 39 publications

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“…Oncogenic MLL-fusion proteins often hijack essential molecular mechanisms during leukemogenesis 6 . Recently, a considerable amount of studies have revealed that MLL and its chaperones are required for genomic integrity in MLL-r leukemia 10,27,28,29,30,31 and lead to chemoresistance 32 . For example, SETD1A is required for survival of AML cells depending on its FLOS domain but not the enzymatic SET domain 10 .…”

Section: Discussionmentioning

confidence: 99%

“…The FLOS domain of SETD1A acts as a cyclin-K-binding site that is responsible for chromosomal recruitment of cyclin K and for DNA-repair-associated gene expression 10 . In addition, SETD1A is found functionally found to interact with the DNA damage repair protein RAD18 to safeguard genome stability 30 . These data suggest a pivotal role of DNA damage response for MLL-fusion-driven leukemia.…”

Section: Discussionmentioning

confidence: 99%

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Anlotinib suppresses MLL-rearranged acute myeloid leukemia cell growth through inhibiting SETD1A/AKT-mediated DNA damage response

Chen

Feng

Fang

et al. 2020

Preprint

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Background: Leukemias driven by chromosomal translocation of the mixed-lineage leukemia gene (MLL) are highly prevalent in hematological malignancy. The poor survival rate and lack of an effective targeted therapy for patients with MLL-rearranged (MLL-r) leukemias emphasize an urgent need for improved knowledge and novel therapeutic approaches for these malignancies. In this study, we investigated the potential effectiveness and mechanism of Anlotinib, a novel receptor tyrosine kinase inhibitor, in MLL-r acute myeloid leukemia(AML). Methods: MLL-r AML cell lines were treated with different concentration of Anlotinib, then cell viability, apoptosis and cell cycle were analyzed. Next, the anti-leukemia effect of Anlotinib was further evaluated in vivo in a xenograft model of AML-carrying MLL-rearrangement. Finally, we performed RNA-seq analysis, Gene Set Enrichment Analysis (GSEA) and western bolting to explore the underlying mechanism of the anti-leukemia effect of Anlotinib. Results: Our findings revealed that Anlotinib significantly suppresses the growth, promotes robust apoptosis and induces G2/M arrest in MLL-r AML cells. Moreover, Anlotinib effectively inhibited the growth of MLL-r AML cells in a xenograft murine model. In mechanism, we find that the inhibitive role of Anlotinib in MLL-r AML could be largely attributed to the dysfunction of DNA damage and repair. Furthermore, we confirmed that Anlotinib impaired DNA damage response via inhibiting SETD1A and AKT.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Anlotinib suppresses MLL-rearranged acute myeloid leukemia cell growth through inhibiting SETD1A/AKT-mediated DNA damage response

Chen

Feng

Fang

et al. 2020

Preprint

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“… [ 96 ] MLL4 Cell proliferation Defects in S-Phase progression [ 111 ] Transcriptional coactivator, Pol II loading and eRNA synthesis at enhancers Reduces Pol II density in adjacent gene-bodies. [ 96 ] SETD1A DNA damage response Supresses DDR genes and induces p53-dependent apoptosis/impaired DDR [ 120 , 123 ] Chromosomal alignment and segregation Delayed chromosomal alignment at metaphase plate. Formation of micronuclei.…”

Section: Non-canonical Roles Of Set1 Family Membersmentioning

confidence: 99%

“…Another recent study also implicates SETD1A in DDR [ 123 ]. This report discloses the association of SETD1A methyltransferases to DNA Damage repair protein RAD18.…”

Section: Non-canonical Roles Of Set1 Family Membersmentioning

confidence: 99%

“…Knockdown of SETD1A or RAD18 using siRNA, revealed their mutual regulation, as they downregulated each other’s expression at mRNA and protein levels, without affecting the global histone H3K4me3 levels. These findings suggest SETD1A together with RAD18 congregate to form a complex which is distinct from the conventional COMPASS complex [ 123 ].…”

Section: Non-canonical Roles Of Set1 Family Membersmentioning

confidence: 99%

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SET1/MLL family of proteins: functions beyond histone methylation

2020

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The SET1 family of enzymes are well known for their involvement in the histone 3 lysine 4 (H3K4) methylation, a conserved trait of euchromatin associated with transcriptional activation. These methyltransferases are distinct, and involved in various biological functions in the cell. Impairment in the function of SET1 family members leads to a number of abnormalities such as skeletal and neurological defects, leukaemogenesis and even lethality. Tremendous progress has been made in understanding the unique biological roles and the mechanism of SET1 enzymes in context with H3K4 methylation/canonical functions. However, in recent years, several studies have indicated the novel role of SET1 family proteins, other than H3K4 methylation, which are equally important for cellular functions. In this review, we focus on these non-canonical function of SET1 family members.

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A chromatin perspective on metabolic and genotoxic impacts on hematopoietic stem and progenitor cells

Yang

Jiang

2020

Cell. Mol. Life Sci.

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The fate determination in self-renewal and differentiation of hematopoietic stem and progenitor cells (HSCs and HPCs) is ultimately controlled by gene expression, which is profoundly influenced by the global and local chromatin state. Cellular metabolism directly influences the chromatin state through the dynamic regulation of the enzymatic activities that modify DNA and histones, but also generates genotoxic metabolites that can damage DNA and thus pose threat to the genome integrity. On the other hand, mechanisms modulating the chromatin state impact metabolism by regulating the expression and activities of key metabolic enzymes. Moreover, through regulating either DNA damage response directly or expression of genes involved in this process, chromatin modulators play active and crucial roles in guarding the genome integrity, breaching of which result in defective HSPC function. Therefore, HSPC function is regulated by the dynamic and two-way interactions between metabolism and chromatin. Here, we review recent advances that provide a chromatin perspective on the major impacts the metabolic and genotoxic factors can have on HSPC function and fate determination.

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SETD1A Methyltransferase Is Physically and Functionally Linked to the DNA Damage Repair Protein RAD18

Cited by 20 publications

References 39 publications

Anlotinib suppresses MLL-rearranged acute myeloid leukemia cell growth through inhibiting SETD1A/AKT-mediated DNA damage response

Anlotinib suppresses MLL-rearranged acute myeloid leukemia cell growth through inhibiting SETD1A/AKT-mediated DNA damage response

SET1/MLL family of proteins: functions beyond histone methylation

A chromatin perspective on metabolic and genotoxic impacts on hematopoietic stem and progenitor cells

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