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https://www.readbyqxmd.com/read/29149348/mechanistic-insight-into-the-assembly-of-the-hera-nura-helicase-nuclease-dna-end-resection-complex
#1
Zainab Ahdash, Andy M Lau, Robert Thomas Byrne, Katja Lammens, Alexandra Stüetzer, Henning Urlaub, Paula J Booth, Eamonn Reading, Karl-Peter Hopfner, Argyris Politis
The HerA-NurA helicase-nuclease complex cooperates with Mre11 and Rad50 to coordinate the repair of double-stranded DNA breaks. Little is known, however, about the assembly mechanism and activation of the HerA-NurA. By combining hybrid mass spectrometry with cryo-EM, computational and biochemical data, we investigate the oligomeric formation of HerA and detail the mechanism of nucleotide binding to the HerA-NurA complex from thermophilic archaea. We reveal that ATP-free HerA and HerA-DNA complexes predominantly exist in solution as a heptamer and act as a DNA loading intermediate...
November 16, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/29116362/homologous-recombination-mediated-repair-of-dna-double-strand-breaks-operates-in-mammalian-mitochondria
#2
Sumedha Dahal, Shubham Dubey, Sathees C Raghavan
Mitochondrial DNA is frequently exposed to oxidative damage, as compared to nuclear DNA. Previously, we have shown that while microhomology-mediated end joining can account for DNA deletions in mitochondria, classical nonhomologous DNA end joining, the predominant double-strand break (DSB) repair pathway in nucleus, is undetectable. In the present study, we investigated the presence of homologous recombination (HR) in mitochondria to maintain its genomic integrity. Biochemical studies revealed that HR-mediated repair of DSBs is more efficient in the mitochondria of testes as compared to that of brain, kidney and spleen...
November 7, 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/29065514/the-role-of-mdm2-in-promoting-genome-stability-versus-instability
#3
REVIEW
M Reza Saadatzadeh, Adily N Elmi, Pankita H Pandya, Khadijeh Bijangi-Vishehsaraei, Jixin Ding, Christopher W Stamatkin, Aaron A Cohen-Gadol, Karen E Pollok
In cancer, the mouse double minute 2 (MDM2) is an oncoprotein that contributes to the promotion of cell growth, survival, invasion, and therapeutic resistance. The impact of MDM2 on cell survival versus cell death is complex and dependent on levels of MDM2 isoforms, p53 status, and cellular context. Extensive investigations have demonstrated that MDM2 protein-protein interactions with p53 and other p53 family members (p63 and p73) block their ability to function as transcription factors that regulate cell growth and survival...
October 23, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29059325/dormant-origins-and-fork-protection-mechanisms-rescue-sister-forks-arrested-by-transcription
#4
Alessandra Brambati, Luca Zardoni, Yathish Jagadheesh Achar, Daniele Piccini, Lorenzo Galanti, Arianna Colosio, Marco Foiani, Giordano Liberi
The yeast RNA/DNA helicase Sen1, Senataxin in human, preserves the integrity of replication forks encountering transcription by removing RNA-DNA hybrids. Here we show that, in sen1 mutants, when a replication fork clashes head-on with transcription is arrested and, as a consequence, the progression of the sister fork moving in the opposite direction within the same replicon is also impaired. Therefore, sister forks remain coupled when one of the two forks is arrested by transcription, a fate different from that experienced by forks encountering Double Strand Breaks...
October 20, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/29053959/restoration-of-replication-fork-stability-in-brca1-and-brca2-deficient-cells-by-inactivation-of-snf2-family-fork-remodelers
#5
Angelo Taglialatela, Silvia Alvarez, Giuseppe Leuzzi, Vincenzo Sannino, Lepakshi Ranjha, Jen-Wei Huang, Chioma Madubata, Roopesh Anand, Brynn Levy, Raul Rabadan, Petr Cejka, Vincenzo Costanzo, Alberto Ciccia
To ensure the completion of DNA replication and maintenance of genome integrity, DNA repair factors protect stalled replication forks upon replication stress. Previous studies have identified a critical role for the tumor suppressors BRCA1 and BRCA2 in preventing the degradation of nascent DNA by the MRE11 nuclease after replication stress. Here we show that depletion of SMARCAL1, a SNF2-family DNA translocase that remodels stalled forks, restores replication fork stability and reduces the formation of replication stress-induced DNA breaks and chromosomal aberrations in BRCA1/2-deficient cells...
October 19, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29038466/replication-fork-reversal-triggers-fork-degradation-in-brca2-defective-cells
#6
Sofija Mijic, Ralph Zellweger, Nagaraja Chappidi, Matteo Berti, Kurt Jacobs, Karun Mutreja, Sebastian Ursich, Arnab Ray Chaudhuri, Andre Nussenzweig, Pavel Janscak, Massimo Lopes
Besides its role in homologous recombination, the tumor suppressor BRCA2 protects stalled replication forks from nucleolytic degradation. Defective fork stability contributes to chemotherapeutic sensitivity of BRCA2-defective tumors by yet-elusive mechanisms. Using DNA fiber spreading and direct visualization of replication intermediates, we report that reversed replication forks are entry points for fork degradation in BRCA2-defective cells. Besides MRE11 and PTIP, we show that RAD52 promotes stalled fork degradation and chromosomal breakage in BRCA2-defective cells...
October 16, 2017: Nature Communications
https://www.readbyqxmd.com/read/29038425/mre11-and-exo1-nucleases-degrade-reversed-forks-and-elicit-mus81-dependent-fork-rescue-in-brca2-deficient-cells
#7
Delphine Lemaçon, Jessica Jackson, Annabel Quinet, Joshua R Brickner, Shan Li, Stephanie Yazinski, Zhongsheng You, Grzegorz Ira, Lee Zou, Nima Mosammaparast, Alessandro Vindigni
The breast cancer susceptibility proteins BRCA1 and BRCA2 have emerged as key stabilizing factors for the maintenance of replication fork integrity following replication stress. In their absence, stalled replication forks are extensively degraded by the MRE11 nuclease, leading to chemotherapeutic sensitivity. Here we report that BRCA proteins prevent nucleolytic degradation by protecting replication forks that have undergone fork reversal upon drug treatment. The unprotected regressed arms of reversed forks are the entry point for MRE11 in BRCA-deficient cells...
October 16, 2017: Nature Communications
https://www.readbyqxmd.com/read/29020621/fanconi-anemia-associated-mutations-destabilize-rad51-filaments-and-impair-replication-fork-protection
#8
Karina Zadorozhny, Vincenzo Sannino, Ondrej Beláň, Jarmila Mlčoušková, Mário Špírek, Vincenzo Costanzo, Lumír Krejčí
Fanconi anemia (FA) is a genetic disorder characterized by a defect in DNA interstrand crosslink (ICL) repair, chromosomal instability, and a predisposition to cancer. Recently, two RAD51 mutations were reported to cause an FA-like phenotype. Despite the tight association of FA/HR proteins with replication fork (RF) stabilization during normal replication, it remains unknown how FA-associated RAD51 mutations affect replication beyond ICL lesions. Here, we report that these mutations fail to protect nascent DNA from MRE11-mediated degradation during RF stalling in Xenopus laevis egg extracts...
October 10, 2017: Cell Reports
https://www.readbyqxmd.com/read/29020620/enhancement-of-blm-dna2-mediated-long-range-dna-end-resection-by-ctip
#9
James M Daley, Judit Jimenez-Sainz, Weibin Wang, Adam S Miller, Xiaoyu Xue, Kevin A Nguyen, Ryan B Jensen, Patrick Sung
DNA double-strand break repair by homologous recombination entails the resection of DNA ends to reveal ssDNA tails, which are used to invade a homologous DNA template. CtIP and its yeast ortholog Sae2 regulate the nuclease activity of MRE11 in the initial stage of resection. Deletion of CtIP in the mouse or SAE2 in yeast engenders a more severe phenotype than MRE11 nuclease inactivation, indicative of a broader role of CtIP/Sae2. Here, we provide biochemical evidence that CtIP promotes long-range resection via the BLM-DNA2 pathway...
October 10, 2017: Cell Reports
https://www.readbyqxmd.com/read/29018935/a-curious-new-role-for-mrn-in-schizosaccharomyces-pombe-non-homologous-end-joining
#10
REVIEW
Kurt W Runge, Yanhui Li
Chromosomal breaks can be healed by several repair processes, including one called non-homologous end-joining (NHEJ) where the two broken ends are ligated together with a loss of 0-5 bp of DNA. The protein requirements for NHEJ of cut DNA ends in the budding yeast Saccharomyces cerevisiae include its version of the Mre11-Rad50-Nbs1 (MRN) complex. In contrast, the fission yeast Schizosaccharomyces pombe and mammalian cells do not require MRN for this process. Recent work in S. pombe used transposon excision to generate breaks that were capped by DNA hairpins, which must be opened to produce ligatable ends...
October 10, 2017: Current Genetics
https://www.readbyqxmd.com/read/28977635/homeostatic-nuclear-rage-atm-interaction-is-essential-for-efficient-dna-repair
#11
Varun Kumar, Thomas Fleming, Stefan Terjung, Christian Gorzelanny, Christoffer Gebhardt, Raman Agrawal, Marcus A Mall, Julia Ranzinger, Martin Zeier, Thati Madhusudhan, Satish Ranjan, Berend Isermann, Arthur Liesz, Divija Deshpande, Hans-Ulrich Häring, Subrata K Biswas, Paul R Reynolds, Hans-Peter Hammes, Rainer Peperkok, Peter Angel, Stephan Herzig, Peter P Nawroth
The integrity of genome is a prerequisite for healthy life. Indeed, defects in DNA repair have been associated with several human diseases, including tissue-fibrosis, neurodegeneration and cancer. Despite decades of extensive research, the spatio-mechanical processes of double-strand break (DSB)-repair, especially the auxiliary factor(s) that can stimulate accurate and timely repair, have remained elusive. Here, we report an ATM-kinase dependent, unforeseen function of the nuclear isoform of the Receptor for Advanced Glycation End-products (nRAGE) in DSB-repair...
October 13, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28973445/redundancy-between-nucleases-required-for-homologous-recombination-promotes-parp-inhibitor-resistance-in-the-eukaryotic-model-organism-dictyostelium
#12
Anna-Lena Kolb, Alasdair R Gunn, Nicholas D Lakin
ADP-ribosyltransferases promote repair of DNA single strand breaks and disruption of this pathway by Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) is toxic to cells with defects in homologous recombination (HR). Here, we show that this relationship is conserved in the simple eukaryote Dictyostelium and exploit this organism to define mechanisms that drive resistance of the HR-deficient cells to PARPi. Dictyostelium cells disrupted in exonuclease I, a critical factor for HR, are sensitive to PARPi. Deletion of exo1 prevents the accumulation of Rad51 in chromatin induced by PARPi, resulting in DNA damage being channelled through repair by non-homologous end-joining (NHEJ)...
September 29, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28970327/genetic-separation-of-sae2-nuclease-activity-from-mre11-nuclease-functions-in-budding-yeast
#13
Sucheta Arora, Rajashree A Deshpande, Martin Budd, Judy Campbell, America Revere, Xiaoming Zhang, Kristina H Schmidt, Tanya T Paull
Sae2 promotes the repair of DNA double-strand breaks in Saccharomyces cerevisiae The role of Sae2 is linked to the Mre11/Rad50/Xrs2 (MRX) complex, which is important for the processing of DNA ends into single-stranded substrates for homologous recombination. Sae2 has intrinsic endonuclease activity, but the role of this activity has not been assessed independently from its functions in promoting Mre11 nuclease activity. Here we identify and characterize separation-of-function mutants that lack intrinsic nuclease activity or the ability to promote Mre11 endonucleolytic activity...
October 2, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28967905/akt-overactivation-can-suppress-dna-repair-via-p70s6-kinase-dependent-downregulation-of-mre11
#14
D Piscitello, D Varshney, S Lilla, M G Vizioli, C Reid, V Gorbunova, A Seluanov, D A Gillespie, P D Adams
Deregulated AKT kinase activity due to PTEN deficiency in cancer cells contributes to oncogenesis by incompletely understood mechanisms. Here, we show that PTEN deletion in HCT116 and DLD1 colon carcinoma cells leads to suppression of CHK1 and CHK2 activation in response to irradiation, impaired G2 checkpoint proficiency and radiosensitization. These defects are associated with reduced expression of MRE11, RAD50 and NBS1, components of the apical MRE11/RAD50/NBS1 (MRN) DNA damage response complex. Consistent with reduced MRN complex function, PTEN-deficient cells fail to resect DNA double-strand breaks efficiently after irradiation and show greatly diminished proficiency for DNA repair via the error-free homologous recombination (HR) repair pathway...
October 2, 2017: Oncogene
https://www.readbyqxmd.com/read/28938088/small-molecule-inhibitors-targeting-dna-repair-and-dna-repair-deficiency-in-research-and-cancer-therapy
#15
REVIEW
Sarah R Hengel, M Ashley Spies, Maria Spies
To maintain stable genomes and to avoid cancer and aging, cells need to repair a multitude of deleterious DNA lesions, which arise constantly in every cell. Processes that support genome integrity in normal cells, however, allow cancer cells to develop resistance to radiation and DNA-damaging chemotherapeutics. Chemical inhibition of the key DNA repair proteins and pharmacologically induced synthetic lethality have become instrumental in both dissecting the complex DNA repair networks and as promising anticancer agents...
September 21, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28922417/lingering-single-strand-breaks-trigger-rad51-independent-homology-directed-repair-of-collapsed-replication-forks-in-the-polynucleotide-kinase-phosphatase-mutant-of-fission-yeast
#16
Arancha Sanchez, Mariana C Gadaleta, Oliver Limbo, Paul Russell
The DNA repair enzyme polynucleotide kinase/phosphatase (PNKP) protects genome integrity by restoring ligatable 5'-phosphate and 3'-hydroxyl termini at single-strand breaks (SSBs). In humans, PNKP mutations underlie the neurological disease known as MCSZ, but these individuals are not predisposed for cancer, implying effective alternative repair pathways in dividing cells. Homology-directed repair (HDR) of collapsed replication forks was proposed to repair SSBs in PNKP-deficient cells, but the critical HDR protein Rad51 is not required in PNKP-null (pnk1Δ) cells of Schizosaccharomyces pombe...
September 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28916659/hybrid-of-dna-targeting-chlorambucil-with-pt-iv-species-to-reverse-drug-resistance
#17
Feihong Chen, Gang Xu, Xiaodong Qin, Xiufeng Jin, Shaohua Gou
Two hybrids of Pt(IV) species were designed and prepared by addition of a chlorambucil unit to the axial positions of the Pt(IV) complexes derived from DN603 and DN604. In vitro studies of two hybrids against two pairs of cisplatin sensitive and resistant cancer cell lines indicated that compound 5 had superior antitumor activity to cisplatin and chlorambucil via suppressing DNA damage repair to reverse drug resistance. Mechanistic investigation suggested that the potent antitumor activity of compound 5 arose from its major suppression of CK2-mediated MRE11-RAD50-NBS1(MRN) complex promotion of DNA double-strand break (DSB) repair...
November 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28894029/pari-regulates-stalled-replication-fork-processing-to-maintain-genome-stability-upon-replication-stress-in-mice
#18
Ayako L Mochizuki, Ami Katanaya, Eri Hayashi, Mihoko Hosokawa, Emiko Moribe, Akira Motegi, Masamichi Ishiai, Minoru Takata, Gen Kondoh, Hitomi Watanabe, Norio Nakatsuji, Shinichiro Chuma
DNA replication is frequently perturbed by intrinsic, as well as extrinsic, genotoxic stress. At damaged forks, DNA replication and repair activities require proper coordination to maintain genome integrity. We show here that PARI antirecombinase plays an essential role in modulating the initial response to replication stress in mice. PARI is functionally dormant at replisomes during normal replication, but upon replication stress, it enhances nascent-strand shortening that is regulated by RAD51 and MRE11. PARI then promotes double-strand break induction, followed by new origin firing instead of replication restart...
December 1, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28886051/the-mre11-a470-alleles-influence-the-hereditability-and-the-segregation-of-telosomes-in-saccharomyces-cerevisiae
#19
In-Joon Baek, Daniel S Moss, Arthur J Lustig
Telomeres, the nucleoprotein complexes at the termini of linear chromosomes, are essential for the processes of end replication, end protection, and chromatin segregation. The Mre11 complex is involved in multiple cellular roles in DNA repair and structure in the regulation and function of telomere size homeostasis. In this study, we characterize yeast telomere chromatin structure, phenotypic heritability, and chromatin segregation in both wild-type [MRE11] and A470 motif alleles. MRE11 strains confer a telomere size of 300 base pairs of G+T irregular simple sequence repeats...
2017: PloS One
https://www.readbyqxmd.com/read/28867292/single-molecule-imaging-reveals-how-mre11-rad50-nbs1-initiates-dna-break-repair
#20
Logan R Myler, Ignacio F Gallardo, Michael M Soniat, Rajashree A Deshpande, Xenia B Gonzalez, Yoori Kim, Tanya T Paull, Ilya J Finkelstein
DNA double-strand break (DSB) repair is essential for maintaining our genomes. Mre11-Rad50-Nbs1 (MRN) and Ku70-Ku80 (Ku) direct distinct DSB repair pathways, but the interplay between these complexes at a DSB remains unclear. Here, we use high-throughput single-molecule microscopy to show that MRN searches for free DNA ends by one-dimensional facilitated diffusion, even on nucleosome-coated DNA. Rad50 binds homoduplex DNA and promotes facilitated diffusion, whereas Mre11 is required for DNA end recognition and nuclease activities...
September 7, 2017: Molecular Cell
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