Blockade of the LRP16-PKR-NF-κB signaling axis sensitizes colorectal carcinoma cells to DNA-damaging cytotoxic therapy

Li, Xiaolei; Wu, Zhiqiang; An, Xingwei; Mei, Qian; Bai, Miaomiao; Hanski, Leena; Li, Xiang; Ahola, Tero; Han, Weidong

doi:10.7554/elife.27301

Cited by 21 publications

(21 citation statements)

References 69 publications

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“…For instance, MacroD1 has been shown to bind and regulate proteins such as the transcription factors ERα, AR and NF-κB ( Han et al, 2007 ; Yang et al, 2009 ; Wu et al, 2011 ). More recently, MacroD1 has been shown to bind and selectively activate, the primarily cytosolic protein ( Jeffrey et al, 1995 ), Protein Kinase R (PKR) ( Li et al, 2017 ). In this study we have shown that endogenous MacroD1 is highly enriched in and primarily localizes to mitochondria.…”

Section: Discussionmentioning

confidence: 99%

MacroD1 Is a Promiscuous ADP-Ribosyl Hydrolase Localized to Mitochondria

Agnew¹,

Munnur²,

Crawford³

et al. 2018

Front. Microbiol.

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MacroD1 is a macrodomain containing protein that has mono-ADP-ribose hydrolase enzymatic activity toward several ADP-ribose adducts. Dysregulation of MacroD1 expression has been shown to be associated with the pathogenesis of several forms of cancer. To date, the physiological functions and sub-cellular localization of MacroD1 are unclear. Previous studies have described nuclear and cytosolic functions of MacroD1. However, in this study we show that endogenous MacroD1 protein is highly enriched within mitochondria. We also show that MacroD1 is highly expressed in human and mouse skeletal muscle. Furthermore, we show that MacroD1 can efficiently remove ADP-ribose from 5′ and 3′-phosphorylated double stranded DNA adducts in vitro. Overall, we have shown that MacroD1 is a mitochondrial protein with promiscuous enzymatic activity that can target the ester bonds of ADP-ribosylated phosphorylated double-stranded DNA ends. These findings have exciting implications for MacroD1 and ADP-ribosylation within the regulation of mitochondrial function and DNA-damage in vivo.

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Section: Discussionmentioning

confidence: 99%

MacroD1 Is a Promiscuous ADP-Ribosyl Hydrolase Localized to Mitochondria

Agnew¹,

Munnur²,

Crawford³

et al. 2018

Front. Microbiol.

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“…Several lines of evidence indicate that MacroD1 is involved in several important signaling pathways: In breast cancer-derived MCF-7 cells, MacroD1 expression is induced by estrogenic hormones in an estrogen receptor alpha (ERα)-dependent manner and subsequently acts as a cofactor for ERα and the androgen receptor (Han et al 2007;Yang et al 2009). In response to DNA double-strand breaks, MacroD1 is activated and enriched in the cytosol, which stimulates prosurvival and antiapoptotic functions of the dimeric (p65/p50) transcription factor NF-κB (Li et al 2017). MacroD1 stimulates the activity of NF-κB through the interaction with p65 and UXT, a transcription factor coregulator (Wu et al 2011(Wu et al , 2015.…”

Section: Macrod1 and Macrod2mentioning

confidence: 99%

(ADP-ribosyl)hydrolases: structure, function, and biology

2020

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ADP-ribosylation is an intricate and versatile posttranslational modification involved in the regulation of a vast variety of cellular processes in all kingdoms of life. Its complexity derives from the varied range of different chemical linkages, including to several amino acid side chains as well as nucleic acids termini and bases, it can adopt. In this review, we provide an overview of the different families of (ADP-ribosyl)hydrolases. We discuss their molecular functions, physiological roles, and influence on human health and disease. Together, the accumulated data support the increasingly compelling view that (ADP-ribosyl)hydrolases are a vital element within ADP-ribosyl signaling pathways and they hold the potential for novel therapeutic approaches as well as a deeper understanding of ADP-ribosylation as a whole.

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“…This might result in cytoplasmic and nuclear localisation, similar to our observation with the N-terminally truncated mutant that no longer is mitochondrial. Alternatively, some of these nuclear interactions may result from the fusion of an N-terminal tag 31,34,58 , which can result in an inaccessible MTS leading to aberrant nuclear localisation, as seen in our live-cell imaging (Fig. 2b).…”

Section: Discussionmentioning

confidence: 93%

Comparative analysis of MACROD1, MACROD2 and TARG1 expression, localisation and interactome

Žaja

Aydin

Lippok

et al. 2020

Sci Rep

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The posttranslational modification ADP-ribosylation is involved in many cellular processes, with distinct roles for poly- and mono(ADP-ribosyl)ation (PAR- and MARylation, respectively). Reversibility of intracellular MARylation was demonstrated with the discovery of MACROD1, MACROD2 and TARG1, three macrodomain-containing enzymes capable of reversing MARylation of proteins and RNA. While the three enzymes have identical activities in vitro, their roles in cells are unclear and published data are partially contradictory, possibly due to a lack of validated reagents. We developed monoclonal antibodies to study these proteins and analysed their tissue distribution and intracellular localisation. MACROD1 is most prevalent in mitochondria of skeletal muscle, MACROD2 localises to nucleo- and cytoplasm and is found so far only in neuroblastoma cells, whereas the more ubiquitously expressed TARG1 is present in nucleoplasm, nucleolus and stress granules. Loss of MACROD1 or loss of TARG1 leads to disruption of mitochondrial or nucleolar morphology, respectively, hinting at their importance for these organelles. To start elucidating the underlying mechanisms, we have mapped their interactomes using BioID. The cellular localisation of interactors supports the mitochondrial, nucleolar and stress granule localisation of MACROD1 and TARG1, respectively. Gene ontology analysis suggests an involvement of MACROD1 and TARG1 in RNA metabolism in their respective compartments. The detailed description of the hydrolases’ expression, localisation and interactome presented here provides a solid basis for future work addressing their physiological function in more detail.

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Blockade of the LRP16-PKR-NF-κB signaling axis sensitizes colorectal carcinoma cells to DNA-damaging cytotoxic therapy

Cited by 21 publications

References 69 publications

MacroD1 Is a Promiscuous ADP-Ribosyl Hydrolase Localized to Mitochondria

MacroD1 Is a Promiscuous ADP-Ribosyl Hydrolase Localized to Mitochondria

(ADP-ribosyl)hydrolases: structure, function, and biology

Comparative analysis of MACROD1, MACROD2 and TARG1 expression, localisation and interactome

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