219 research outputs found
Multiple roles of DNA2 nuclease/helicase in DNA metabolism, genome stability and human diseases
DNA2 nuclease/helicase is a structure-specific nuclease, 5′-to-3′ helicase, and DNA-dependent ATPase. It is involved in multiple DNA metabolic pathways, including Okazaki fragment maturation, replication of ‘difficult-to-replicate’ DNA regions, end resection, stalled replication fork processing, and mitochondrial genome maintenance. The participation of DNA2 in these different pathways is regulated by its interactions with distinct groups of DNA replication and repair proteins and by post-translational modifications. These regulatory mechanisms induce its recruitment to specific DNA replication or repair complexes, such as DNA replication and end resection machinery, and stimulate its efficient cleavage of various structures, for example, to remove RNA primers or to produce 3′ overhangs at telomeres or double-strand breaks. Through these versatile activities at replication forks and DNA damage sites, DNA2 functions as both a tumor suppressor and promoter. In normal cells, it suppresses tumorigenesis by maintaining the genomic integrity. Thus, DNA2 mutations or functional deficiency may lead to cancer initiation. However, DNA2 may also function as a tumor promoter, supporting cancer cell survival by counteracting replication stress. Therefore, it may serve as an ideal target to sensitize advanced DNA2-overexpressing cancers to current chemo- and radiotherapy regimens
The DNA–protein interaction modes of FEN-1 with gap substrates and their implication in preventing duplication mutations
Flap endonuclease-1 (FEN-1) is a structure-specific nuclease best known for its involvement in RNA primer removal and long-patch base excision repair. This enzyme is known to possess 5′-flap endo- (FEN) and 5′–3′ exo- (EXO) nuclease activities. Recently, FEN-1 has been reported to also possess a gap endonuclease (GEN) activity, which is possibly involved in apoptotic DNA fragmentation and the resolution of stalled DNA replication forks. In the current study, we compare the kinetics of these activities to shed light on the aspects of DNA structure and FEN-1 DNA-binding elements that affect substrate cleavage. By using DNA binding deficient mutants of FEN-1, we determine that the GEN activity is analogous to FEN activity in that the single-stranded DNA region of DNA substrates interacts with the clamp region of FEN-1. In addition, we show that the C-terminal extension of human FEN-1 likely interacts with the downstream duplex portion of all substrates. Taken together, a substrate-binding model that explains how FEN-1, which has a single active center, can have seemingly different activities is proposed. Furthermore, based on the evidence that GEN activity in complex with WRN protein cleaves hairpin and internal loop substrates, we suggest that the GEN activity may prevent repeat expansions and duplication mutations
Determining the Solution Space of Vertex-Cover by Interactions and Backbones
To solve the combinatorial optimization problems especially the minimal
Vertex-cover problem with high efficiency, is a significant task in theoretical
computer science and many other subjects. Aiming at detecting the solution
space of Vertex-cover, a new structure named interaction between nodes is
defined and discovered for random graph, which results in the emergence of the
frustration and long-range correlation phenomenon. Based on the backbones and
interactions with a node adding process, we propose an Interaction and Backbone
Evolution Algorithm to achieve the reduced solution graph, which has a direct
correspondence to the solution space of Vertex-cover. By this algorithm, the
whole solution space can be obtained strictly when there is no leaf-removal
core on the graph and the odd cycles of unfrozen nodes bring great obstacles to
its efficiency. Besides, this algorithm possesses favorable exactness and has
good performance on random instances even with high average degrees. The
interaction with the algorithm provides a new viewpoint to solve Vertex-cover,
which will have a wide range of applications to different types of graphs,
better usage of which can lower the computational complexity for solving
Vertex-cover
Supported monodisperse Pt nanoparticles from [Pt-3(CO)(3)(mu(2)-CO)(3)](5)(2-) clusters for investigating support-Pt interface effect in catalysis
MOST of China [2011CB932403]; NSFC [21131005, 21021061, 20925103, 20923004]; Fok Ying Tung Education Foundation [121011]Here we present a surfactant-free strategy to prepare supported monodisperse Pt nanoparticles from molecular [Pt-3(CO)(3)(mu(2)-CO)(3)](5)(2-) clusters. The strategy allows facile deposition of same-sized Pt nanoparticles on various oxide supports to unambiguously study the interface effect between noble metal and metal oxide in catalysis. In this study, Fe2O3 is demonstrated to be a superior support over TiO2, CeO2 and SiO2 to prepare highly active supported Pt nanoparticles for CO oxidation, which indicates that the interfaces between Pt and iron oxide are the active sites for O-2 activation and CO oxidation
RAD51 and mitotic function of MUS81 are essential for recovery from low-dose of camptothecin in the absence of the WRN exonuclease
Stabilization of stalled replication forks prevents excessive fork reversal or degradation, which can undermine genome integrity. The WRN protein is unique among the other human RecQ family members to possess exonuclease activity. However, the biological role of the WRN exonuclease is poorly defined. Recently, the WRN exonuclease has been linked to protection of stalled forks from degradation. Alternative processing of perturbed forks has been associated to chemoresistance of BRCA-deficient cancer cells. Thus, we used WRN exonuclease-deficiency as a model to investigate the fate of perturbed forks undergoing degradation, but in a BRCA wild-type condition. We find that, upon treatment with clinically-relevant nanomolar doses of the Topoisomerase I inhibitor camptothecin, loss of WRN exonuclease stimulates fork inactivation and accumulation of parental gaps, which engages RAD51. Such mechanism affects reinforcement of CHK1 phosphorylation and causes persistence of RAD51 during recovery from treatment. Notably, in WRN exonuclease-deficient cells, persistence of RAD51 correlates with elevated mitotic phosphorylation of MUS81 at Ser87, which is essential to prevent excessive mitotic abnormalities. Altogether, these findings indicate that aberrant fork degradation, in the presence of a wild-type RAD51 axis, stimulates RAD51-mediated post-replicative repair and engagement of the MUS81 complex to limit genome instability and cell death
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