Latest Issue
Issue 1 ， 2021
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Mass spectrometry-based protein‒protein interaction techniques and their applications in studies of DNA damage repair
Abstract：Proteins are major functional units that are tightly connected to form complex and dynamic networks. These networks enable cells and organisms to operate properly and respond efficiently to environmental cues. Over the past decades, many biochemical methods have been developed to search for protein-binding partners in order to understand how protein networks are constructed and connected. At the same time, rapid development in proteomics and mass spectrometry (MS) techniques makes it possible to identify interacting proteins and build comprehensive protein‒protein interaction networks. The resulting interactomes and networks have proven informative in the investigation of biological functions, such as in the field of DNA damage repair. In recent years, a number of proteins involved in DNA damage response and DNA repair pathways have been uncovered with MS-based protein‒protein interaction studies. As the technologies for enriching associated proteins and MS become more sophisticated, the studies of protein‒protein interactions are entering a new era. In this review, we summarize the strategies and recent developments for exploring protein‒protein interaction. In addition, we discuss the application of these tools in the investigation of protein‒protein interaction networks involved in DNA damage response and DNA repair.Keywords：Protein‒protein interaction;Interactome;Proteomics;Mass spectrometry;DNA repair;DNA damage response- 196
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Published：2021-05-07 -
ADP-ribosylhydrolases: from DNA damage repair to COVID-19
Abstract：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).Keywords：DNA damage repair;Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2);Adenosine diphosphate (ADP)-ribosylation;Macrodomain;ADP-ribosylhydrolase;deADP-ribosylation- 165
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Published：2021-05-07 -
MRN complex is an essential effector of DNA damage repair
Abstract：Genome stability can be threatened by both endogenous and exogenous agents. Organisms have evolved numerous mechanisms to repair DNA damage, including homologous recombination (HR) and non-homologous end joining (NHEJ). Among the factors associated with DNA repair, the MRE11-RAD50-NBS1 (MRN) complex (MRE11-RAD50-XRS2 in Saccharomyces cerevisiae) plays important roles not only in DNA damage recognition and signaling but also in subsequent HR or NHEJ repair. Upon detecting DNA damage, the MRN complex activates signaling molecules, such as the protein kinase ataxia-telangiectasia mutated (ATM), to trigger a broad DNA damage response, including cell cycle arrest. The nuclease activity of the MRN complex is responsible for DNA end resection, which guides DNA repair to HR in the presence of sister chromatids. The MRN complex is also involved in NHEJ, and has a species-specific role in hairpin repair. This review focuses on the structure of the MRN complex and its function in DNA damage repair.Keywords：DNA damage repair;MRE11-RAD50-NBS1 (MRN) complex;Homologous recombination;Non-homologous end joining- 168
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Published：2021-05-07 -
Regulation of DNA double-strand break repair pathway choice: a new focus on 53BP1
Abstract：Maintenance of cellular homeostasis and genome integrity is a critical responsibility of DNA double-strand break (DSB) signaling. P53-binding protein 1 (53BP1) plays a critical role in coordinating the DSB repair pathway choice and promotes the non-homologous end-joining (NHEJ)-mediated DSB repair pathway that rejoins DSB ends. New insights have been gained into a basic molecular mechanism that is involved in 53BP1 recruitment to the DNA lesion and how 53BP1 then recruits the DNA break-responsive effectors that promote NHEJ-mediated DSB repair while inhibiting homologous recombination (HR) signaling. This review focuses on the up- and downstream pathways of 53BP1 and how 53BP1 promotes NHEJ-mediated DSB repair, which in turn promotes the sensitivity of poly(ADP-ribose) polymerase inhibitor (PARPi) in BRCA1-deficient cancers and consequently provides an avenue for improving cancer therapy strategies.Keywords：P53-binding protein 1 (53BP1);DNA double-strand break (DSB);Non-homologous end-joining (NHEJ);Homologous recombination (HR);Poly(ADP-ribose) polymerase inhibitor (PARPi)- 148
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Published：2021-05-07 -
DNA alkylation lesion repair: outcomes and implications in cancer chemotherapy
Abstract：Alkylated DNA lesions, induced by both exogenous chemical agents and endogenous metabolites, represent a major form of DNA damage in cells. The repair of alkylation damage is critical in all cells because such damage is cytotoxic and potentially mutagenic. Alkylation chemotherapy is a major therapeutic modality for many tumors, underscoring the importance of the repair pathways in cancer cells. Several different pathways exist for alkylation repair, including base excision and nucleotide excision repair, direct reversal by methyl-guanine methyltransferase (MGMT), and dealkylation by the AlkB homolog (ALKBH) protein family. However, maintaining a proper balance between these pathways is crucial for the favorable response of an organism to alkylating agents. Here, we summarize the progress in the field of DNA alkylation lesion repair and describe the implications for cancer chemotherapy.Keywords：Alkylation repair;Base excision repair;Methyl-guanine methyltransferase (MGMT);AlkB homolog (ALKBH)- 67
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Published：2021-05-07 -
Role of deubiquitinating enzymes in DNA double-strand break repair
Abstract：DNA is the hereditary material in humans and almost all other organisms. It is essential for maintaining accurate transmission of genetic information. In the life cycle, DNA replication, cell division, or genome damage, including that caused by endogenous and exogenous agents, may cause DNA aberrations. Of all forms of DNA damage, DNA double-strand breaks (DSBs) are the most serious. If the repair function is defective, DNA damage may cause gene mutation, genome instability, and cell chromosome loss, which in turn can even lead to tumorigenesis. DNA damage can be repaired through multiple mechanisms. Homologous recombination (HR) and non-homologous end joining (NHEJ) are the two main repair mechanisms for DNA DSBs. Increasing amounts of evidence reveal that protein modifications play an essential role in DNA damage repair. Protein deubiquitination is a vital post-translational modification which removes ubiquitin molecules or polyubiquitinated chains from substrates in order to reverse the ubiquitination reaction. This review discusses the role of deubiquitinating enzymes (DUBs) in repairing DNA DSBs. Exploring the molecular mechanisms of DUB regulation in DSB repair will provide new insights to combat human diseases and develop novel therapeutic approaches.Keywords：Deubiquitinating enzymes (DUBs);DNA double-strand breaks (DSBs);DNA repair;Non-homologous end joining (NHEJ);Homologous recombination (HR)- 148
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Published：2021-05-07 -
Target binding and residence: a new determinant of DNA double-strand break repair pathway choice in CRISPR/Cas9 genome editing
Abstract：The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) is widely used for targeted genomic and epigenomic modifications and imaging in cells and organisms, and holds tremendous promise in clinical applications. The efficiency and accuracy of the technology are partly determined by the target binding affinity and residence time of Cas9-single-guide RNA (sgRNA) at a given site. However, little attention has been paid to the effect of target binding affinity and residence duration on the repair of Cas9-induced DNA double-strand breaks (DSBs). We propose that the choice of DSB repair pathway may be altered by variation in the binding affinity and residence duration of Cas9-sgRNA at the cleaved target, contributing to significantly heterogeneous mutations in CRISPR/Cas9 genome editing. Here, we discuss the effect of Cas9-sgRNA target binding and residence on the choice of DSB repair pathway in CRISPR/Cas9 genome editing, and the opportunity this presents to optimize Cas9-based technology.Keywords：CRISPR/Cas9 genome editing;Double-strand break (DSB) repair pathway choice;Target binding affinity;Target residence- 47
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Published：2021-05-07
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