Protein–protein and protein–chromatin interactions of LEDGF/p75 as novel drug targets

Blokken, Jolien; Rijck, Jan De; Christ, Frauke; Debyser, Zeger

doi:10.1016/j.ddtec.2017.11.002

Cited by 24 publications

(32 citation statements)

References 70 publications

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“…Mutations in the PWWP domain are associated with a variety of human diseases. Lens epithelial cellderived growth factor plays an important role in tethering HIV-1 cDNA to human chromatin through the PWWP domain (Blokken et al, 2017). Disruption of the PWWP domain of the WHSC1 protein results in lymphoid multiple myeloma (Stec et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Role of hepatoma‐derived growth factor in promoting de novo lipogenesis and tumorigenesis in hepatocellular carcinoma

et al. 2018

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Although identified as a growth factor, the mechanism by which hepatoma‐derived growth factor (HDGF) promotes cancer development remains unclear. We found that nuclear but not cytoplasmic HDGF is closely associated with prognosis of hepatocellular carcinoma (HCC). RNA‐sequencing analysis further demonstrated that the nuclear role of HDGF involved regulation of transcription of lipid metabolism genes. HDGF‐induced expression of lipogenic genes was mainly associated with activation of sterol regulatory element binding protein (SREBP) transcription factor. Coexpression of SREBP‐1 and nuclear HDGF predicts poor prognosis for HCC. In addition, by changing the first amino acid of the PWWP domain from proline to alanine, the type of PWWP domain changed from P‐ to A‐type, resulting in inability to induce SREBP‐1‐mediated gene transcription. The type of PWWP domain affects the recruitment of the C‐terminal binding protein‐1 transcriptional repressor on the promoter of the lipogenic gene. Our data indicate that HDGF acts as a coactivator of SREBP1‐mediated transcription of lipogenic genes. The PWWP domain is crucial for HDGF to promote lipogenesis. Moreover, transcriptional regulation of nuclear HDGF plays important roles in the development of HCC.

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Section: Discussionmentioning

confidence: 99%

Role of hepatoma‐derived growth factor in promoting de novo lipogenesis and tumorigenesis in hepatocellular carcinoma

et al. 2018

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“…The known functions of the N-and C-terminal regions are listed DFS70/LEDGF interacts with the human immunodeficiency virus 1 integrase (HIV-IN) and serves as a tethering factor to facilitate viral DNA integration into host chromatin. This seminal finding paved the way for numerous studies that not only elucidated the role of this transcriptional co-activator in HIV-1 integration but stimulated research into its basic biology (reviewed in [42][43][44][45]). For instance, these studies have revealed that the DFS70/LEDGF PWWP domain facilitates the recognition of di-or tri-methylated lysine 36 in histone H3 (H3K36me2/3), which serves as a marker of actively transcribed genes [46,47].…”

Section: Hsp27mentioning

confidence: 99%

“…It was recently established that the ability to bind H3K36me2/3 allows DFS70/ LEDGF and the hepatoma derived growth factor protein HRP2/HDGF2 to work in concert to enable RNA pol II to overcome nucleosome-induced barrier to transcription observed in differentiated cells that no longer express the FACT (facilitates chromatin transcription) protein complex [48]. This property also allows DFS70/ LEDGF to tether its interacting partners, including HIV-IN, to transcriptionally active sites in the chromatin [45,46]. HIV-IN interacts with a C-terminal domain structure in DFS70/LEDGF, designated the integrase binding domain (IBD), that is involved in the efficient integration and replication of HIV-1 into host chromatin [49].…”

Section: Hsp27mentioning

confidence: 99%

“…2). The IBD serves as a hub for protein-protein interactions that, together with the PWWP domain, facilitates the tethering of HIV-IN and transcription factors to RNA pol II complexes at transcriptionally active sites [42][43][44][45][46][49][50][51][52]. In addition to HIV-IN, a number of interacting partners of DFS70/LEDGF that bind to the IBD have been identified (Table 2).…”

Section: Hsp27mentioning

confidence: 99%

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Twenty years of research on the DFS70/LEDGF autoantibody-autoantigen system: many lessons learned but still many questions

Ortiz-Hernández

Sanchez-Hernández

Casiano

2020

Autoimmun Highlights

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The discovery and initial characterization 20 years ago of antinuclear autoantibodies (ANAs) presenting a dense fine speckled (DFS) nuclear pattern with strong staining of mitotic chromosomes, detected by indirect immunofluorescence assay in HEp-2 cells (HEp-2 IIFA test), has transformed our view on ANAs. Traditionally, ANAs have been considered as reporters of abnormal immunological events associated with the onset and progression of systemic autoimmune rheumatic diseases (SARD), also called ANA-associated rheumatic diseases (AARD), as well as clinical biomarkers for the differential diagnosis of these diseases. However, based on our current knowledge, it is not apparent that autoantibodies presenting the DFS IIF pattern fall into these categories. These antibodies invariably target a chromatin-associated protein designated as dense fine speckled protein of 70 kD (DFS70), also known as lens epitheliumderived growth factor protein of 75 kD (LEDGF/p75) and PC4 and SFRS1 Interacting protein 1 (PSIP1). This multi-functional protein, hereafter referred to as DFS70/LEDGF, plays important roles in the formation of transcription complexes in active chromatin, transcriptional activation of specific genes, regulation of mRNA splicing, DNA repair, and cellular survival against stress. Due to its multiple functions, it has emerged as a key protein contributing to several human pathologies, including acquired immunodeficiency syndrome (AIDS), leukemia, cancer, ocular diseases, and Rett syndrome. Unlike other ANAs, "monospecific" anti-DFS70/LEDGF autoantibodies (only detectable ANA in serum) are not associated with SARD and have been detected in healthy individuals and some patients with non-SARD inflammatory conditions. These observations have led to the hypotheses that these antibodies could be considered as negative biomarkers of SARD and might even play a protective or beneficial role. In spite of 20 years of research on this autoantibody-autoantigen system, its biological and clinical significance still remains enigmatic. Here we review the current state of knowledge of this system, focusing on the lessons learned and posing emerging questions that await further scrutiny as we continue our quest to unravel its significance and potential clinical and therapeutic utility.

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“…The C-terminus uniquely present in the LEDGF/p75 isoform contains the HIV-1 integrase binding domain and the region recognized by human anti-LEDGF/p75 autoantibodies, whereas LEDGF/p52 has eight distinctive intron-derived C-terminal amino acids [138][139][140]. As a transcriptional coactivator, LEDGF/p75 recognizes di-and tri-methyl K36 of histone H3, recruiting protein complexes at active chromatin [139,141], but it was also reported a sequence-specific binding to heat shock elements (HSE; nGAAn) and stress-related elements (STRE; T/AGGGG) [142]. The LEDGF/p75 protein is ubiquitously present in mammalian cells and it has been implicated in inflammatory and autoimmune conditions.…”

Section: Lens Epithelium-derived Growth Factor (Ledgf)mentioning

confidence: 99%

Transcription Factors in Cancer: When Alternative Splicing Determines Opposite Cell Fates

Belluti

Rigillo

Imbriano

2020

Cells

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Alternative splicing (AS) is a finely regulated mechanism for transcriptome and proteome diversification in eukaryotic cells. Correct balance between AS isoforms takes part in molecular mechanisms that properly define spatiotemporal and tissue specific transcriptional programs in physiological conditions. However, several diseases are associated to or even caused by AS alterations. In particular, multiple AS changes occur in cancer cells and sustain the oncogenic transcriptional program. Transcription factors (TFs) represent a key class of proteins that control gene expression by direct binding to DNA regulatory elements. AS events can generate cancer-associated TF isoforms with altered activity, leading to sustained proliferative signaling, differentiation block and apoptosis resistance, all well-known hallmarks of cancer. In this review, we focus on how AS can produce TFs isoforms with opposite transcriptional activities or antagonistic functions that severely impact on cancer biology. This summary points the attention to the relevance of the analysis of TFs splice variants in cancer, which can allow patients stratification despite the presence of interindividual genetic heterogeneity. Recurrent TFs variants that give advantage to specific cancer types not only open the opportunity to use AS transcripts as clinical biomarkers but also guide the development of new anti-cancer strategies in personalized medicine.

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Protein–protein and protein–chromatin interactions of LEDGF/p75 as novel drug targets

Cited by 24 publications

References 70 publications

Role of hepatoma‐derived growth factor in promoting de novo lipogenesis and tumorigenesis in hepatocellular carcinoma

Role of hepatoma‐derived growth factor in promoting de novo lipogenesis and tumorigenesis in hepatocellular carcinoma

Twenty years of research on the DFS70/LEDGF autoantibody-autoantigen system: many lessons learned but still many questions

Transcription Factors in Cancer: When Alternative Splicing Determines Opposite Cell Fates

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