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1.
Cells ; 10(2)2021 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-33578760

RESUMO

Adenosine diphosphate ribosylation (ADP-ribosylation; ADPr), the addition of ADP-ribose moieties onto proteins and nucleic acids, is a highly conserved modification involved in a wide range of cellular functions, from viral defence, DNA damage response (DDR), metabolism, carcinogenesis and neurobiology. Here we study MACROD1 and MACROD2 (mono-ADP-ribosylhydrolases 1 and 2), two of the least well-understood ADPr-mono-hydrolases. MACROD1 has been reported to be largely localized to the mitochondria, while the MACROD2 genomic locus has been associated with various neurological conditions such as autism, attention deficit hyperactivity disorder (ADHD) and schizophrenia; yet the potential significance of disrupting these proteins in the context of mammalian behaviour is unknown. Therefore, here we analysed both Macrod1 and Macrod2 gene knockout (KO) mouse models in a battery of well-defined, spontaneous behavioural testing paradigms. Loss of Macrod1 resulted in a female-specific motor-coordination defect, whereas Macrod2 disruption was associated with hyperactivity that became more pronounced with age, in combination with a bradykinesia-like gait. These data reveal new insights into the importance of ADPr-mono-hydrolases in aspects of behaviour associated with both mitochondrial and neuropsychiatric disorders.


Assuntos
Comportamento Animal , Hidrolases de Éster Carboxílico/deficiência , Enzimas Reparadoras do DNA/deficiência , Hidrolases/deficiência , Animais , Peso Corporal , Hidrolases de Éster Carboxílico/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Feminino , Marcha , Técnicas de Inativação de Genes , Genótipo , Hidrolases/metabolismo , Masculino , Camundongos Knockout , Atividade Motora , Reprodutibilidade dos Testes
2.
Front Microbiol ; 9: 20, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29410655

RESUMO

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.

3.
Crit Rev Biochem Mol Biol ; 53(1): 64-82, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29098880

RESUMO

Proper and timely regulation of cellular processes is fundamental to the overall health and viability of organisms across all kingdoms of life. Thus, organisms have evolved multiple highly dynamic and complex biochemical signaling cascades in order to adapt and survive diverse challenges. One such method of conferring rapid adaptation is the addition or removal of reversible modifications of different chemical groups onto macromolecules which in turn induce the appropriate downstream outcome. ADP-ribosylation, the addition of ADP-ribose (ADPr) groups, represents one of these highly conserved signaling chemicals. Herein we outline the writers, erasers and readers of ADP-ribosylation and dip into the multitude of cellular processes they have been implicated in. We also review what we currently know on how specificity of activity is ensured for this important modification.


Assuntos
ADP-Ribosilação , ADP Ribose Transferases/metabolismo , Adenosina Difosfato Ribose/metabolismo , Animais , Dano ao DNA , Humanos , Transdução de Sinais
4.
Semin Cell Dev Biol ; 63: 102-113, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27677453

RESUMO

Compaction mode of chromatin and chromatin highly organised structures regulate gene expression. Posttranslational modifications, histone variants and chromatin remodelers modulate the compaction, structure and therefore function of specific regions of chromatin. The generation of poly(ADP-ribose) (PAR) is emerging as one of the key signalling events on sites undergoing chromatin structure modulation. PAR is generated locally in response to stresses. These include genotoxic stress but also differentiation signals, metabolic and hormonal cues. A pictures emerges in which transient PAR formation is essential to orchestrate chromatin remodelling and transcription factors allowing the cell to adapt to alteration in its environment. This review summarizes the diverse factors of ADP-ribosylation in the adaptive regulation of chromatin structure and transcription.


Assuntos
Montagem e Desmontagem da Cromatina , Poli(ADP-Ribose) Polimerases/metabolismo , Transcrição Gênica , ADP-Ribosilação , Animais , Cromatina/metabolismo , Reparo do DNA/genética , Humanos
5.
Curr Pharm Des ; 17(6): 618-30, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21391912

RESUMO

p53, the "guardian of the genome" and the most mutated gene in cancer presents a considerable therapeutic opportunity as well as a challenge. In the past decade, several therapeutic strategies have been developed that aim to take advantage of a wealth of knowledge about p53, including insights into the biology and patho-biology of p53. Nevertheless, considerable challenges remain, not least as a result of tissue- and cancer-specific differences in p53 regulation and/or function. p53 does not act in the same manner in all tissues or in the cancers arising from them. Nor is p53 regulated in the same way in the wide variety of tissues from which cancers develop. Therefore, potential strategies for therapeutic targeting need to be tailored to each tumour/tissue type. This review summarises some of these tissue- and cancer-specific issues to suggest how different strategies are required for cancers arising from different tissues and to illustrate the complexities of therapeutic targeting of p53.


Assuntos
Apoptose , Morte Celular , Genes p53 , Neoplasias/tratamento farmacológico , Proteína Supressora de Tumor p53/metabolismo , Humanos , Terapia de Alvo Molecular , Neoplasias/classificação , Neoplasias/genética , Proteína Supressora de Tumor p53/genética
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