Last update 01 Nov 2024

L3MBTL3

Last update 01 Nov 2024

Basic Info

Synonyms

H-l(3)mbt-like protein 3, KIAA1798, l(3)mbt-like 3 (Drosophila)

+ [8]

Introduction

Is a negative regulator of Notch target genes expression, required for RBPJ-mediated transcriptional repression (PubMed:29030483). It recruits KDM1A to Notch-responsive elements and promotes KDM1A-mediated H3K4me demethylation (PubMed:29030483). Involved in the regulation of ubiquitin-dependent degradation of a set of methylated non-histone proteins, including SOX2, DNMT1 and E2F1. It acts as an adapter recruiting the CRL4-DCAF5 E3 ubiquitin ligase complex to methylated target proteins (PubMed:30442713, PubMed:29691401). Required for normal maturation of myeloid progenitor cells (By similarity).

Drugs associated with L3MBTL3

UNC1679

Target

L3MBTL3

Mechanism

L3MBTL3 inhibitors

Active Org.

The University of North Carolina at Chapel Hill

Originator Org.

The University of North Carolina at Chapel Hill

Active Indication-

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

UNC1215

Target

L3MBTL3

Mechanism

L3MBTL3 inhibitors

Active Org.

The University of North Carolina at Chapel Hill

Originator Org.

The University of North Carolina at Chapel Hill

Active Indication-

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with L3MBTL3

100 Translational Medicine associated with L3MBTL3

0 Patents (Medical) associated with L3MBTL3

Literatures (Medical) associated with L3MBTL3

01 Feb 2023·Heliyon

L3MBTL3 is induced by HIF-1α and fine tunes the HIF-1α degradation under hypoxia in vitro

Article

Author: Wang, Di ; Lai, Dongming ; Wang, Mengdong ; Lang, Yue ; Tang, Jun ; Zhang, Rui ; Xiao, Chenglu ; Shao, Anwen

HIF-1α plays a crucial part in hypoxia response by transcriptionally upregulating genes to adapt the hypoxic condition. HIF-1α is under severe cellular control as its exceptional activation is always associated with tumorigenesis and tumor progression. Here, we report L3MBTL3 serves as a novel negative regulator of HIF-1α. It is upregulated during hypoxia and acts as a transcriptional target of HIF-1α. In the nuclei, L3MBTL3 makes an interaction with HIF-1α and promotes its ubiquitination and degradation. These findings indicate L3MBTL3 forms a negative feedback loop with HIF-1α in vitro to dampen the hypoxic response.

09 Dec 2022·Nucleic Acids Research

The structure, binding and function of a Notch transcription complex involving RBPJ and the epigenetic reader protein L3MBTL3

Article

Author: Park, Sung-Soo ; Ferrante, Francesca ; Giaimo, Benedetto Daniele ; Bartkuhn, Marek ; Borggrefe, Tilman ; Hall, Daniel ; Kovall, Rhett A ; Hemmer, Wiebke ; Friedrich, Tobias ; Rual, Jean-François ; Yuan, Zhenyu ; Oswald, Franz

AbstractThe Notch pathway transmits signals between neighboring cells to elicit downstream transcriptional programs. Notch is a major regulator of cell fate specification, proliferation, and apoptosis, such that aberrant signaling leads to a pleiotropy of human diseases, including developmental disorders and cancers. The pathway signals through the transcription factor CSL (RBPJ in mammals), which forms an activation complex with the intracellular domain of the Notch receptor and the coactivator Mastermind. CSL can also function as a transcriptional repressor by forming complexes with one of several different corepressor proteins, such as FHL1 or SHARP in mammals and Hairless in Drosophila. Recently, we identified L3MBTL3 as a bona fide RBPJ-binding corepressor that recruits the repressive lysine demethylase LSD1/KDM1A to Notch target genes. Here, we define the RBPJ-interacting domain of L3MBTL3 and report the 2.06 Å crystal structure of the RBPJ–L3MBTL3–DNA complex. The structure reveals that L3MBTL3 interacts with RBPJ via an unusual binding motif compared to other RBPJ binding partners, which we comprehensively analyze with a series of structure-based mutants. We also show that these disruptive mutations affect RBPJ and L3MBTL3 function in cells, providing further insights into Notch mediated transcriptional regulation.

06 Oct 2022·EMBO reports

Lint‐O cooperates with L(3)mbt in target gene suppression to maintain homeostasis in fly ovary and brain

Article

Author: Miyoshi, Keita ; Yoshitane, Hikari ; Fukada, Yoshitaka ; Moritoh, Mai ; Yamanaka, Soichiro ; Siomi, Mikiko C ; Saito, Kuniaki ; Yamamoto‐Matsuda, Hitomi

AbstractLoss‐of‐function mutations in Drosophila lethal(3)malignant brain tumor [l(3)mbt] cause ectopic expression of germline genes and brain tumors. Loss of L(3)mbt function in ovarian somatic cells (OSCs) aberrantly activates germ‐specific piRNA amplification and leads to infertility. However, the underlying mechanism remains unclear. Here, ChIP‐seq for L(3)mbt in cultured OSCs and RNA‐seq before and after L(3)mbt depletion shows that L(3)mbt genomic binding is not necessarily linked to gene regulation and that L(3)mbt controls piRNA pathway genes in multiple ways. Lack of known L(3)mbt co‐repressors, such as Lint‐1, has little effect on the levels of piRNA amplifiers. Identification of L(3)mbt interactors in OSCs and subsequent analysis reveals CG2662 as a novel co‐regulator of L(3)mbt, termed “L(3)mbt interactor in OSCs” (Lint‐O). Most of the L(3)mbt‐bound piRNA amplifier genes are also bound by Lint‐O in a similar fashion. Loss of Lint‐O impacts the levels of piRNA amplifiers, similar to the lack of L(3)mbt. The lint‐O‐deficient flies exhibit female sterility and tumorous brains. Thus, L(3)mbt and its novel co‐suppressor Lint‐O cooperate in suppressing target genes to maintain homeostasis in the ovary and brain.

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L3MBTL3

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