RESUMEN
Adenosine diphosphate (ADP)-ribosylation is a unique post-translational modification that regulates many biological processes, such as DNA damage repair. During DNA repair, ADP-ribosylation needs to be reversed by ADP-ribosylhydrolases. A group of ADP-ribosylhydrolases have a catalytic domain, namely the macrodomain, which is conserved in evolution from prokaryotes to humans. Not all macrodomains remove ADP-ribosylation. One set of macrodomains loses enzymatic activity and only binds to ADP-ribose (ADPR). Here, we summarize the biological functions of these macrodomains in DNA damage repair and compare the structure of enzymatically active and inactive macrodomains. Moreover, small molecular inhibitors have been developed that target macrodomains to suppress DNA damage repair and tumor growth. Macrodomain proteins are also expressed in pathogens, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, these domains may not be directly involved in DNA damage repair in the hosts or pathogens. Instead, they play key roles in pathogen replication. Thus, by targeting macrodomains it may be possible to treat pathogen-induced diseases, such as coronavirus disease 2019 (COVID-19).
Asunto(s)
Humanos , ADP-Ribosilación , COVID-19/metabolismo , Reparación del ADN/fisiología , Evolución Molecular , Modelos Biológicos , Modelos Moleculares , N-Glicosil Hidrolasas/metabolismo , Poli(ADP-Ribosa) Polimerasas/metabolismo , Dominios Proteicos , SARS-CoV-2/patogenicidadRESUMEN
The morbidity of neurodegenerative diseases are increased in recent years, however, the treatment is limited. Poly ADP-ribosylation (PARylation) is a post-translational modification of protein that catalyzed by poly(ADP-ribose) polymerase (PARP). Studies have shown that PARylation is involved in many neurodegenerative diseases such as stroke, Parkinson's diseases, Alzheimer's disease, amyotrophic lateral sclerosis and so on, by affecting intracellular translocation of protein molecules, protein aggregation, protein activity, and cell death. PARP inhibitors have showed neuroprotective efficacy for neurodegenerative diseases in pre-clinical studies and phase Ⅰ clinical trials. To find new PARP inhibitors with more specific effects and specific pharmacokinetic characteristics will be the new direction for the treatment of neurodegenerative diseases. This paper reviews the recent progress on PARylation in neurodegenerative diseases.