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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 127 records · Page 7
All sourcesNASA NTRSDOE OSTI
DOE OSTI2017

p53R2 regulates thioredoxin reductase activity through interaction with TrxR2

Ribonucleotide reductase small subunit p53R2 is a member of the ribonucleotide reductase family that supplies dNTPs for nuclear and mitochondrial DNA replication and repair. Here, we have identified a mitochondrial thioredoxin reductase 2 (TrxR2) as a novel p53R2-binding protein. We demonstrated a direct interaction between the two, and observed that p53R2 stimulated the enzymatic activity of TrxR in vitro. Moreover, TrxR2 activity was significantly lower in p53R2 knockdown cells, and increased when p53R2 was overexpressed, effects that were independent of p53. Furthermore, p53R2 knockdown suppressed UV-induced TrxR activity. These findings suggest that p53R2 acts as a positive regulator of TrxR2 activity in mitochondria both under normal physiological conditions and during the cellular response to DNA damage. - Highlights: • P53R2 binds to thioredoxin reductase 2 (TrxR2) in vivo and in vitro. • P53R2 enhances TrxR activity. • P53R2 regulates TrxR activity in a p53-independent manner. • P53R2 acts as a positive regulator of TrxR2 activity under both normal and DNA damage conditions.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Crystal structure of the histone heterodimer containing histone variant H2A.Bbd

H2A.Bbd, the most divergent histone variant among all known H2A type histones, is involved in gene transcription, spermiogenesis, DNA replication and RNA splicing. Incorporation of H2A.Bbd-H2B dimer, a fundamental unit of H2A.Bbd nucleosome, modulate structures of nucleosome or chromatin, but the underlying mechanism remains elusive. Here we determined a crystal structure of H2A.Bbd-H2B dimer at 2.6 Å resolution. Although the H2A.Bbd-H2B dimer structure largely resembles that of H2A-H2B, substitution of H2A αC helix residues by H2A.Bbd counterparts lead to the transition of a long αC-helix to the short 3{sub 10}-helix, likely owing to the rearrangement of the hydrogen-bond network. Moreover, structural comparison revealed a strikingly altered electrostatic potential surface for H2A.Bbd-H2B dimer displaying a diminished DNA binding capability. Our study provides the first high-resolution structure of histone variant H2A.Bbd and shed a light on biological function of H2A.Bbd.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2013

Proteotoxic stress induced by Autographa californica nucleopolyhedrovirus infection of Spodoptera frugiperda Sf9 cells

Baculovirus AcMNPV causes proteotoxicity in Sf9 cells as revealed by accumulation of ubiquitinated proteins and aggresomes in the course of infection. Inhibition of proteasomes by lactacystin increased markedly the stock of ubiquitinated proteins indicating a primary role of proteasomes in detoxication. The proteasomes were present in Sf9 cells as 26S and 20S complexes whose protease activity did not change during infection. Proteasome inhibition caused a delay in the initiation of viral DNA replication suggesting an important role of proteasomes at early stages in infection. However, lactacystin did not affect ongoing replication indicating that active proteasomes are not required for genome amplification. At late stages in infection (24-48 hpi), aggresomes containing the ubiquitinated proteins and HSP/HSC70s showed gradual fusion with the vacuole-like structures identified as lysosomes by antibody to cathepsin D. This result suggests that lysosomes may assist in protection against proteotoxicity caused by baculoviruses absorbing the ubiquitinated proteins.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Resveratrol mediated cell death in cigarette smoke transformed breast epithelial cells is through induction of p21Waf1/Cip1 and inhibition of long patch base excision repair pathway

Cigarette smoking is a key factor for the development and progression of different cancers including mammary tumor in women. Resveratrol (Res) is a promising natural chemotherapeutic agent that regulates many cellular targets including p21, a cip/kip family of cyclin kinase inhibitors involved in DNA damage-induced cell cycle arrest and blocking of DNA replication and repair. We have recently shown that cigarette smoke condensate (CSC) prepared from commercially available Indian cigarette can cause neoplastic transformation of normal breast epithelial MCF-10A cell. Here we studied the mechanism of Res mediated apoptosis in CSC transformed (MCF-10A-Tr) cells in vitro and in vivo. Res mediated apoptosis in MCF-10A-Tr cells was a p21 dependent event. It increased the p21 protein expression in MCF-10A-Tr cells and MCF-10A-Tr cells-mediated tumors in xenograft mice. Res treatment reduced the tumor size(s) and expression of anti-apoptotic proteins (e.g. PI3K, AKT, NFκB) in solid tumor. The expressions of cell cycle regulatory (Cyclins, CDC-2, CDC-6, etc.), BER associated (Pol-β, Pol-δ, Pol-ε, Pol-η, RPA, Fen-1, DNA-Ligase-I, etc.) proteins and LP-BER activity decreased in MCF-10A-Tr cells but remain significantly unaltered in isogenic p21 null MCF-10A-Tr cells after Res treatment. Interestingly, no significant changes were noted in SP-BER activity in both the cell lines after Res exposure. Finally, it was observed that increased p21 blocks the LP-BER in MCF-10A-Tr cells by increasing its interaction with PCNA via competing with Fen-1 after Res treatment. Thus, Res caused apoptosis in CSC-induced cancer cells by reduction of LP-BER activity and this phenomenon largely depends on p21. - Highlights: • Resveratrol (Res) caused reduction of MCF-10A-Tr cell growth by inducing apoptosis. • Res caused cell cycle arrest and DNA damage in p21 dependent manner. • Res mediated LP-BER reduction in MCF-10A-Tr cells was a p21 dependent phenomenon. • Res inhibits BER and PI3K, AKT, and NFκB protein expressions in tumor and xenografts. • Res-induced-p21 inhibited DNA repair by modulating Fen-1 binding to PCNA complex.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2012

Structure and Biochemical Activities of Escherichia coli MgsA

Bacterial 'maintenance of genome stability protein A' (MgsA) and related eukaryotic enzymes play important roles in cellular responses to stalled DNA replication processes. Sequence information identifies MgsA enzymes as members of the clamp loader clade of AAA{sup +} proteins, but structural information defining the family has been limited. Here, the x-ray crystal structure of Escherichia coli MgsA is described, revealing a homotetrameric arrangement for the protein that distinguishes it from other clamp loader clade AAA{sup +} proteins. Each MgsA protomer is composed of three elements as follows: ATP-binding and helical lid domains (conserved among AAA{sup +} proteins) and a tetramerization domain. Although the tetramerization domains bury the greatest amount of surface area in the MgsA oligomer, each of the domains participates in oligomerization to form a highly intertwined quaternary structure. Phosphate is bound at each AAA{sup +} ATP-binding site, but the active sites do not appear to be in a catalytically competent conformation due to displacement of Arg finger residues. E. coli MgsA is also shown to form a complex with the single-stranded DNA-binding protein through co-purification and biochemical studies. MgsA DNA-dependent ATPase activity is inhibited by single-stranded DNA-binding protein. Together, these structural and biochemical observations provide insights into the mechanisms of MgsA family AAA{sup +} proteins.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2014

Comparative genomic and proteomic analyses of Clostridium acetobutylicum Rh8 and its parent strain DSM 1731 revealed new understandings on butanol tolerance

Highlights: • Genomes of a butanol tolerant strain and its parent strain were deciphered. • Comparative genomic and proteomic was applied to understand butanol tolerance. • None differentially expressed proteins have mutations in its corresponding genes. • Mutations in ribosome might be responsible for the global difference of proteomics. - Abstract: Clostridium acetobutylicum strain Rh8 is a butanol-tolerant mutant which can tolerate up to 19 g/L butanol, 46% higher than that of its parent strain DSM 1731. We previously performed comparative cytoplasm- and membrane-proteomic analyses to understand the mechanism underlying the improved butanol tolerance of strain Rh8. In this work, we further extended this comparison to the genomic level. Compared with the genome of the parent strain DSM 1731, two insertion sites, four deletion sites, and 67 single nucleotide variations (SNVs) are distributed throughout the genome of strain Rh8. Among the 67 SNVs, 16 SNVs are located in the predicted promoters and intergenic regions; while 29 SNVs are located in the coding sequence, affecting a total of 21 proteins involved in transport, cell structure, DNA replication, and protein translation. The remaining 22 SNVs are located in the ribosomal genes, affecting a total of 12 rRNA genes in different operons. Analysis of previous comparative proteomic data indicated that none of the differentially expressed proteins have mutations in its corresponding genes. Rchange Algorithms analysis indicated that the mutations occurred in the ribosomal genes might change the ribosome RNA thermodynamic characteristics, thus affect the translation strength of these proteins. Take together, the improved butanol tolerance of C. acetobutylicum strain Rh8 might be acquired through regulating the translational process to achieve different expression strength of genes involved in butanol tolerance.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Both H4K20 mono-methylation and H3K56 acetylation mark transcription-dependent histone turnover in fission yeast

Nucleosome dynamics facilitated by histone turnover is required for transcription as well as DNA replication and repair. Histone turnover is often associated with various histone modifications such as H3K56 acetylation (H3K56Ac), H3K36 methylation (H3K36me), and H4K20 methylation (H4K20me). In order to correlate histone modifications and transcription-dependent histone turnover, we performed genome wide analyses for euchromatic regions in G2/M-arrested fission yeast. The results show that transcription-dependent histone turnover at 5′ promoter and 3′ termination regions is directly correlated with the occurrence of H3K56Ac and H4K20 mono-methylation (H4K20me1) in actively transcribed genes. Furthermore, the increase of H3K56Ac and H4K20me1 and antisense RNA production was observed in the absence of the histone H3K36 methyltransferase Set2 and histone deacetylase complex (HDAC) that are involved in the suppression of histone turnover within the coding regions. These results together indicate that H4K20me1 as well as H3K56Ac are bona fide marks for transcription-dependent histone turnover in fission yeast.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2012

High Performance Computing Facility Operational Assessment, CY 2011 Oak Ridge Leadership Computing Facility

Oak Ridge National Laboratory's Leadership Computing Facility (OLCF) continues to deliver the most powerful resources in the U.S. for open science. At 2.33 petaflops peak performance, the Cray XT Jaguar delivered more than 1.4 billion core hours in calendar year (CY) 2011 to researchers around the world for computational simulations relevant to national and energy security; advancing the frontiers of knowledge in physical sciences and areas of biological, medical, environmental, and computer sciences; and providing world-class research facilities for the nation's science enterprise. Users reported more than 670 publications this year arising from their use of OLCF resources. Of these we report the 300 in this review that are consistent with guidance provided. Scientific achievements by OLCF users cut across all range scales from atomic to molecular to large-scale structures. At the atomic scale, researchers discovered that the anomalously long half-life of Carbon-14 can be explained by calculating, for the first time, the very complex three-body interactions between all the neutrons and protons in the nucleus. At the molecular scale, researchers combined experimental results from LBL's light source and simulations on Jaguar to discover how DNA replication continues past a damaged site so a mutation can be repaired later. Other researchers combined experimental results from ORNL's Spallation Neutron Source and simulations on Jaguar to reveal the molecular structure of ligno-cellulosic material used in bioethanol production. This year, Jaguar has been used to do billion-cell CFD calculations to develop shock wave compression turbo machinery as a means to meet DOE goals for reducing carbon sequestration costs. General Electric used Jaguar to calculate the unsteady flow through turbo machinery to learn what efficiencies the traditional steady flow assumption is hiding from designers. Even a 1% improvement in turbine design can save the nation billions of gallons of fuel.

99 GENERAL AND MISCELLANEOUS↗
DOE OSTI2018

CBX3 promotes proliferation and regulates glycolysis via suppressing FBP1 in pancreatic cancer

More and more evidence has demonstrated that Chromobox protein homolog 3(CBX3) has an important role in carcinogenesis by regulating several mechanisms, such as heterochromatin formation, gene silencing, DNA replication and repair. However, its role in pancreatic cancer has seldom been discussed. In the present study, we silenced CBX3 expression in pancreatic cancer cell lines and identified the positive roles of CBX3 in cancer cell proliferation. Furthermore, we demonstrated that silencing CBX3 in pancreatic cancer cells inhibited aerobic glycolysis, the basis for providing cancer cells with building blocks for macromolecule synthesis and ATP that required. To search for the underlying molecular mechanism, we turned to examine the impact of CBX3 on the expression of FBP1, a negative regulator of aerobic glycolysis in pancreatic cancer and indicated that CBX3 negatively regulated FBP1 expression. Silencing FBP1 expression attenuated the decrease in glycolytic capacity that caused by CBX3 knockdown in pancreatic cancer cells. Taken together, these data reveal that CBX3 serves as a positive regulator of aerobic glycolysis via suppressing of the FBP1 in pancreatic cancer cells. Disrupting the CBX3-FBP1 signaling axis would be effective to treat pancreatic cancer and prevent aerobic glycolysis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

The KYxxL motif in Rad17 protein is essential for the interaction with the 9–1–1 complex

ATR-dependent DNA damage checkpoint is the major DNA damage checkpoint against UV irradiation and DNA replication stress. The Rad17–RFC and Rad9–Rad1–Hus1 (9–1–1) complexes interact with each other to contribute to ATR signaling, however, the precise regulatory mechanism of the interaction has not been established. Here, we identified a conserved sequence motif, KYxxL, in the AAA+ domain of Rad17 protein, and demonstrated that this motif is essential for the interaction with the 9–1–1 complex. We also show that UV-induced Rad17 phosphorylation is increased in the Rad17 KYxxL mutants. These data indicate that the interaction with the 9–1–1 complex is not required for Rad17 protein to be an efficient substrate for the UV-induced phosphorylation. Our data also raise the possibility that the 9–1–1 complex plays a negative regulatory role in the Rad17 phosphorylation. We also show that the nucleotide-binding activity of Rad17 is required for its nuclear localization. - Highlights: • We have identified a conserved KYxxL motif in Rad17 protein. • The KYxxL motif is crucial for the interaction with the 9–1–1 complex. • The KYxxL motif is dispensable or inhibitory for UV-induced Rad17 phosphorylation. • Nucleotide binding of Rad17 is required for its nuclear localization.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Selenium utilization in thioredoxin and catalytic advantage provided by selenocysteine

Thioredoxin (Trx) is a major thiol-disulfide reductase that plays a role in many biological processes, including DNA replication and redox signaling. Although selenocysteine (Sec)-containing Trxs have been identified in certain bacteria, their enzymatic properties have not been characterized. In this study, we expressed a selenoprotein Trx from Treponema denticola, an oral spirochete, in Escherichia coli and characterized this selenoenzyme and its natural cysteine (Cys) homologue using E. coli Trx1 as a positive control. {sup 75}Se metabolic labeling and mutation analyses showed that the SECIS (Sec insertion sequence) of T. denticola selenoprotein Trx is functional in the E. coli Sec insertion system with specific selenium incorporation into the Sec residue. The selenoprotein Trx exhibited approximately 10-fold higher catalytic activity than the Sec-to-Cys version and natural Cys homologue and E. coli Trx1, suggesting that Sec confers higher catalytic activity on this thiol-disulfide reductase. Kinetic analysis also showed that the selenoprotein Trx had a 30-fold higher K{sub m} than Cys-containing homologues, suggesting that this selenoenzyme is adapted to work efficiently with high concentrations of substrate. Collectively, the results of this study support the hypothesis that selenium utilization in oxidoreductase systems is primarily due to the catalytic advantage provided by the rare amino acid, Sec. - Highlights: • The first characterization of a selenoprotein Trx is presented. • The selenoenzyme Trx exhibits 10-fold higher catalytic activity than Cys homologues. • Se utilization in Trx is primarily due to the catalytic advantage provided by Sec residue.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2012

Crystal Structure of UBA2[superscript ufd]-Ubc9: Insights into E1-E2 Interactions in Sumo Pathways

Canonical ubiquitin-like proteins (UBLs) such as ubiquitin, Sumo, NEDD8, and ISG15 are ligated to targets by E1-E2-E3 multienzyme cascades. The Sumo cascade, conserved among all eukaryotes, regulates numerous biological processes including protein localization, transcription, DNA replication, and mitosis. Sumo conjugation is initiated by the heterodimeric Aos1-Uba2 E1 enzyme (in humans called Sae1-Uba2), which activates Sumo's C-terminus, binds the dedicated E2 enzyme Ubc9, and promotes Sumo C-terminal transfer between the Uba2 and Ubc9 catalytic cysteines. To gain insights into details of E1-E2 interactions in the Sumo pathway, we determined crystal structures of the C-terminal ubiquitin fold domain (ufd) from yeast Uba2 (Uba2{sup ufd}), alone and in complex with Ubc9. The overall structures of both yeast Uba2{sup ufd} and Ubc9 superimpose well on their individual human counterparts, suggesting conservation of fundamental features of Sumo conjugation. Docking the Uba2{sup ufd}-Ubc9 and prior full-length human Uba2 structures allows generation of models for steps in Sumo transfer from Uba2 to Ubc9, and supports the notion that Uba2 undergoes remarkable conformational changes during the reaction. Comparisons to previous structures from the NEDD8 cascade demonstrate that UBL cascades generally utilize some parallel E1-E2 interaction surfaces. In addition, the structure of the Uba2{sup ufd}-Ubc9 complex reveals interactions unique to Sumo E1 and E2. Comparison with a previous Ubc9-E3 complex structure demonstrates overlap between Uba2 and E3 binding sites on Ubc9, indicating that loading with Sumo and E3-catalyzed transfer to substrates are strictly separate steps. The results suggest mechanisms establishing specificity and order in Sumo conjugation cascades.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2012

Flap endonucleases pass 5'-flaps through a flexible arch using a disorder-thread-order mechanism to confer specificity for free 5'-ends

Flap endonucleases (FENs), essential for DNA replication and repair, recognize and remove RNA or DNA 5'-flaps. Related to FEN specificity for substrates with free 5'-ends, but controversial, is the role of the helical arch observed in varying conformations in substrate-free FEN structures. Conflicting models suggest either 5'-flaps thread through the arch, which when structured can only accommodate single-stranded (ss) DNA, or the arch acts as a clamp. Here we show that free 5'-termini are selected using a disorder-thread-order mechanism. Adding short duplexes to 5'-flaps or 3'-streptavidin does not markedly impair the FEN reaction. In contrast, reactions of 5'-streptavidin substrates are drastically slowed. However, when added to premixed FEN and 5'-biotinylated substrate, streptavidin is not inhibitory and complexes persist after challenge with unlabelled competitor substrate, regardless of flap length or the presence of a short duplex. Cross-linked flap duplexes that cannot thread through the structured arch react at modestly reduced rate, ruling out mechanisms involving resolution of secondary structure. Combined results explain how FEN avoids cutting template DNA between Okazaki fragments and link local FEN folding to catalysis and specificity: the arch is disordered when flaps are threaded to confer specificity for free 5'-ends, with subsequent ordering of the arch to catalyze hydrolysis.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2015

NUCKS1 is a novel RAD51AP1 paralog important for homologous recombination and genome stability

NUCKS1 (nuclear casein kinase and cyclin-dependent kinase substrate 1) is a 27 kD chromosomal, vertebrate-specific protein, for which limited functional data exist. Here, we demonstrate that NUCKS1 shares extensive sequence homology with RAD51AP1 (RAD51 associated protein 1), suggesting that these two proteins are paralogs. Similar to the phenotypic effects of RAD51AP1 knockdown, we find that depletion of NUCKS1 in human cells impairs DNA repair by homologous recombination (HR) and chromosome stability. Depletion of NUCKS1 also results in greatly increased cellular sensitivity to mitomycin C (MMC), and in increased levels of spontaneous and MMC-induced chromatid breaks. NUCKS1 is critical to maintaining wild type HR capacity, and, as observed for a number of proteins involved in the HR pathway, functional loss of NUCKS1 leads to a slow down in DNA replication fork progression with a concomitant increase in the utilization of new replication origins. Interestingly, recombinant NUCKS1 shares the same DNA binding preference as RAD51AP1, but binds to DNA with reduced affinity when compared to RAD51AP1. Finally, our results show that NUCKS1 is a chromatin-associated protein with a role in the DNA damage response and in HR, a DNA repair pathway critical for tumor suppression.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2016

The Epigenomic Landscape of Prokaryotes

DNA methylation acts in concert with restriction enzymes to protect the integrity of prokaryotic genomes. Studies in a limited number of organisms suggest that methylation also contributes to prokaryotic genome regulation, but the prevalence and properties of such non-restriction-associated methylation systems remain poorly understood. Here, we used single molecule, real-time sequencing to map DNA modifications including m6A, m4C, and m5C across the genomes of 230 diverse bacterial and archaeal species. We observed DNA methylation in nearly all (93%) organisms examined, and identified a total of 834 distinct reproducibly methylated motifs. This data enabled annotation of the DNA binding specificities of 620 DNA Methyltransferases (MTases), doubling known specificities for previously hard to study Type I, IIG and III MTases, and revealing their extraordinary diversity. Strikingly, 48% of organisms harbor active Type II MTases with no apparent cognate restriction enzyme. These active ‘orphan’ MTases are present in diverse bacterial and archaeal phyla and show motif specificities and methylation patterns consistent with functions in gene regulation and DNA replication. Our results reveal the pervasive presence of DNA methylation throughout the prokaryotic kingdoms, as well as the diversity of sequence specificities and potential functions of DNA methylation systems.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2016

Regulation of infection efficiency in a globally abundant marine Bacteriodetes virus

Microbes impact human health and disease, industrial processes and natural ecosystems, but do so under the influence of viruses. Problematically, knowledge of viral infection efficiencies and outcomes (e.g. lysis, lysogeny) derives from few model systems that over-represent efficient, lytic infections and under-represent virus-host natural diversity. Here we sought to understand how infection efficiency is regulated in an environmental Bacteroidetes virus that represents a globally abundant viral group and has drastically different infection efficiencies when infecting two nearly identical bacterial strains. To this end, we quantified bacterial virus (phage) and host DNA, transcripts and phage particles throughout the infection of both bacterial hosts. While the phage transcriptome was similar during both infections, host transcriptional differences appeared to have altered infection efficiency. Specifically, host transcriptomes suggested that the phage failed to repress early host expression in the inefficient nfection, thereby allowing the host to respond against infection by delaying phage DNA replication and protein translation. Further measurements showed that phage DNA and particle production were delayed (by >30 minutes) and reduced (by >50%) in the inefficient versus efficient infection as the host over-expressed DNA degradation genes and under-expressed translation genes, respectively. Together these results suggest that multiple levels of regulation can impact infection efficiencies as failure to repress host transcription allowed the host to defend against both phage DNA and protein production. Given that this phage type is ubiquitous and abundant in the global oceans and that variably efficient viral infections are likely common in any ecosystem with varying phage-host abundances and physiological states, these data provide a critically needed foundation for understanding and modeling viral infection efficiency in nature.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

Processing of DNA single-strand breaks with oxidatively damaged ends by LIG1

Abstract DNA ligase 1 (LIG1) seals broken strand breaks by joining two adjacent ends during DNA replication and repair transactions. We previously reported atomic-level insight into the strategies that LIG1 uses to discriminate mismatches or ribonucleotides. However, how LIG1 processes strand breaks with oxidatively damaged ends in the absence and presence of a “wrong” sugar remains unknown. Here, we determined the crystal structures of LIG1/nick DNA complexes with 3′-8-oxodG and 3′-8-oxorG templating A or C during the pre- and post-catalytic steps of the ligation reaction. Our structures demonstrated differences in the distances at the +1 and +2 nucleotides relative to the 3′-end of the nick and a shift in the template base position to accommodate the oxidative lesion depending on the dual coding potential of 8-oxoG, which forms Hoogsteen or Watson–Crick base pairing in -syn or -anti conformation. Furthermore, these structural adjustments lead to mutagenic ligation or non-mutagenic end joining of the nick substrates. Overall, our findings provide mechanistic insight into how LIG1 processes nicks harboring oxidative damage and ribonucleotides to ensure fidelity at the final ligation step of DNA repair and replication to maintain genome integrity.

Balu, Kanal E [Department of Biochemistry and Mole↗