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https://www.readbyqxmd.com/read/29334356/p53-suppresses-mutagenic-rad52-and-pol%C3%AE-pathways-by-orchestrating-dna-replication-restart-homeostasis
#1
Sunetra Roy, Karl-Heinz Tomaszowski, Jessica W Luzwick, Soyoung Park, Jun Li, Maureen Murphy, Katharina Schlacher
Classically, p53 tumor suppressor acts in transcription, apoptosis, and cell cycle arrest. Yet, replication-mediated genomic instability is integral to oncogenesis, and p53 mutations promote tumor progression and drug-resistance. By delineating human and murine separation-of-function p53 alleles, we find that p53 null and gain-of-function (GOF) mutations exhibit defects in restart of stalled or damaged DNA replication forks driving genomic instability genetically separable from transcription activation. By assaying protein-DNA fork interactions in single cells, we unveil a p53-MLL3-enabled recruitment of MRE11 DNA replication restart nuclease...
January 15, 2018: ELife
https://www.readbyqxmd.com/read/29324736/no-additional-prognostic-value-for-mre11-in-squamous-cell-carcinomas-of-the-anus-treated-with-chemo-radiotherapy
#2
Alexandra K Walker, Christiana Kartsonaki, Elena Collantes, Judith Nicholson, Duncan C Gilbert, Anne E Kiltie
This corrects the article DOI: 10.1038/bjc.2017.188.
January 11, 2018: British Journal of Cancer
https://www.readbyqxmd.com/read/29322791/targeting-rad50-increases-sensitivity-to-radiotherapy-in-colorectal-cancer-cells
#3
C Chen, Y Wang, J F Mei, S S Li, H X Xu, H P Xiong, X H Wang, X He
Radiotherapy resistance remains the major factor limiting the radiotherapy efficacy in colorectal cancer. The Mre11-RAD50-Nbs1 (MRN) complex is known to play a critical role in the DNA double strand breaks (DSBs) repair pathways and thus facilitates radioresistance. Targeting MRN function can sensitize cancer cells to irradiation in some malignancies. In this study, we stably knocked down RAD50 protein in colorectal cancer (CRC) cell lines, HCT116 and DLD1, and evaluated their response to irradiation as well as the DSB repair dynamics...
2018: Neoplasma
https://www.readbyqxmd.com/read/29321179/physiological-protein-blocks-direct-the-mre11-rad50-xrs2-and-sae2-nuclease-complex-to-initiate-dna-end-resection
#4
Giordano Reginato, Elda Cannavo, Petr Cejka
DNA double-strand break repair by homologous recombination is initiated by DNA end resection, which is commenced by the Mre11-Rad50-Xrs2 complex and Sae2 in yeast. Here we report that the nonhomologous end joining factor Ku limits the exonuclease activity of Mre11 and promotes its endonuclease to cleave 5'-terminated DNA strands at break sites. Following initial endonucleolytic cleavage past the obstacle, Exo1 specifically extends the resection track, leading to the generation of long 3' overhangs that are required for homologous recombination...
January 10, 2018: Genes & Development
https://www.readbyqxmd.com/read/29321177/plasticity-of-the-mre11-rad50-xrs2-sae2-nuclease-ensemble-in-the-processing-of-dna-bound-obstacles
#5
Weibin Wang, James M Daley, Youngho Kwon, Danielle S Krasner, Patrick Sung
The budding yeast Mre11-Rad50-Xrs2 (MRX) complex and Sae2 function together in DNA end resection during homologous recombination. Here we show that the Ku complex shields DNA ends from exonucleolytic digestion but facilitates endonucleolytic scission by MRX with a dependence on ATP and Sae2. The incision site is enlarged into a DNA gap via the exonuclease activity of MRX, which is stimulated by Sae2 without ATP being present. RPA renders a partially resected or palindromic DNA structure susceptible to MRX-Sae2, and internal protein blocks also trigger DNA cleavage...
January 10, 2018: Genes & Development
https://www.readbyqxmd.com/read/29317520/atm-directs-dna-damage-responses-and-proteostasis-via-genetically-separable-pathways
#6
Ji-Hoon Lee, Michael R Mand, Chung-Hsuan Kao, Yi Zhou, Seung W Ryu, Alicia L Richards, Joshua J Coon, Tanya T Paull
The protein kinase ATM is a master regulator of the DNA damage response but also responds directly to oxidative stress. Loss of ATM causes ataxia telangiectasia, a neurodegenerative disorder with pleiotropic symptoms that include cerebellar dysfunction, cancer, diabetes, and premature aging. We genetically separated the activation of ATM by DNA damage from that by oxidative stress using separation-of-function mutations. We found that deficient activation of ATM by the Mre11-Rad50-Nbs1 complex and DNA double-strand breaks resulted in loss of cell viability, checkpoint activation, and DNA end resection in response to DNA damage...
January 9, 2018: Science Signaling
https://www.readbyqxmd.com/read/29298824/mof-suppresses-replication-stress-and-contribute-to-resolution-of-stalled-replication-forks
#7
Dharmendra Kumar Singh, Raj K Pandita, Mayank Singh, Sharmistha Chakraborty, Shashank Hambarde, Deepti Ramnarain, Vijaya Charaka, Kazi Mokim Ahmed, Clayton R Hunt, Tej K Pandita
The hMOF protein belongs to the MYST family of histone acetyltransferases and plays a critical role in transcription and the DNA damage response. MOF is essential for cell proliferation, however its role during replication and replicative stress is unknown. Here we demonstrate that cells depleted for MOF and under replicative stress induced by cisplatin, hydroxyurea or camptothecin have reduced survival, a higher frequency of S-phase specific chromosome damage and increased R-loop formation. MOF depletion decreased replication fork speed and, when combined with replicative stress, also increased stalled replication forks as well as new origin firing...
January 3, 2018: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/29285240/molecular-basis-for-the-dna-damage-induction-and-anticancer-activity-of-asymmetrically-substituted-anthrapyridazone-pdz-7
#8
Majus Misiak, Mateusz Heldt, Marlena Szeligowska, Stefania Mazzini, Leonardo Scaglioni, Grzegorz J Grabe, Marcin Serocki, Jan Lica, Marta Switalska, Joanna Wietrzyk, Giovanni L Beretta, Paola Perego, Dominik Zietkowski, Maciej Baginski, Edward Borowski, Andrzej Skladanowski
Anthrapyridazones, imino analogues of anthraquinone, constitute a family of compounds with remarkable anti-cancer activity. To date, over 20 derivatives were studied, of which most displayed nanomolar cytotoxicity towards broad spectrum of cancer cells, including breast, prostate and leukemic ones. BS-154, the most potent derivative, had IC50 values close to 1 nM, however, it was toxic in animal studies. Here, we characterize another anthrapyridazone, PDZ-7, which retains high cytotoxicity while being well tolerated in mice...
December 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/29229926/cell-cycle-dependent-phosphorylation-regulates-recql4-pathway-choice-and-ubiquitination-in-dna-double-strand-break-repair
#9
Huiming Lu, Raghavendra A Shamanna, Jessica K de Freitas, Mustafa Okur, Prabhat Khadka, Tomasz Kulikowicz, Priscella P Holland, Jane Tian, Deborah L Croteau, Anthony J Davis, Vilhelm A Bohr
Pathway choice within DNA double-strand break (DSB) repair is a tightly regulated process to maintain genome integrity. RECQL4, deficient in Rothmund-Thomson Syndrome, promotes the two major DSB repair pathways, non-homologous end joining (NHEJ) and homologous recombination (HR). Here we report that RECQL4 promotes and coordinates NHEJ and HR in different cell cycle phases. RECQL4 interacts with Ku70 to promote NHEJ in G1 when overall cyclin-dependent kinase (CDK) activity is low. During S/G2 phases, CDK1 and CDK2 (CDK1/2) phosphorylate RECQL4 on serines 89 and 251, enhancing MRE11/RECQL4 interaction and RECQL4 recruitment to DSBs...
December 11, 2017: Nature Communications
https://www.readbyqxmd.com/read/29227281/targeting-mcl-1-enhances-dna-replication-stress-sensitivity-to-cancer-therapy
#10
Guo Chen, Andrew T Magis, Ke Xu, Dongkyoo Park, David S Yu, Taofeek K Owonikoko, Gabriel L Sica, Sarah W Satola, Suresh S Ramalingam, Walter J Curran, Paul W Doetsch, Xingming Deng
DNA double-strand breaks (DSBs) are mainly repaired either by homologous recombination (HR) or by nonhomologous end-joining (NHEJ) pathways. Here, we showed that myeloid cell leukemia sequence 1 (Mcl-1) acts as a functional switch in selecting between HR and NHEJ pathways. Mcl-1 was cell cycle-regulated during HR, with its expression peaking in S/G2 phase. While endogenous Mcl-1 depletion reduced HR and enhanced NHEJ, Mcl-1 overexpression resulted in a net increase in HR over NHEJ. Mcl-1 directly interacted with the dimeric Ku protein complex via its Bcl-2 homology 1 and 3 (BH1 and BH3) domains, which are required for Mcl-1 to inhibit Ku-mediated NHEJ...
December 11, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29217481/dna-damage-and-repair-proteins-in-cellular-response-to-sulfur-mustard-in-iranian-veterans-more-than-two-decades-after-exposure
#11
Shahriar Khateri, Mahdi Balali-Mood, Peter Blain, Faith Williams, Paul Jowsey, Mohammad Reza Soroush, Effat Behravan, Mahmood Sadeghi
Delayed effects of sulfur mustard (SM) exposure on the levels of five important damage/repair proteins were investigated in 40 SM-exposed veterans of Iran-Iraq war and 35 unexposed controls. A major DNA damage biomarker protein - phosphorylated H2AX - along with four DNA repair proteins in cell response to the genome damage MRE11, NBS1, RAD51, and XPA were evaluated in blood lymphocytes from the veterans and controls using western blotting. Mean levels of XPA, MRE11, RAD51 and NBS1 were lower in SM-exposed patients and the decrease in NBS1 was significant...
December 4, 2017: Toxicology Letters
https://www.readbyqxmd.com/read/29208713/sbcc-sbcd-and-exoi-process-convergent-forks-to-complete-chromosome-replication
#12
Brian M Wendel, Jessica M Cole, Charmain T Courcelle, Justin Courcelle
SbcC-SbcD are the bacterial orthologs of Mre11-Rad50, a nuclease complex essential for genome stability, normal development, and viability in mammals. In vitro, these enzymes degrade long DNA palindromic structures. When inactivated along with ExoI in Escherichia coli, or Sae2 in eukaryotes, palindromic amplifications arise and propagate in cells. However, long DNA palindromes are not normally found in bacterial or human genomes, leaving the cellular substrates and function of these enzymes unknown. Here, we show that during the completion of DNA replication, convergent replication forks form a palindrome-like structural intermediate that requires nucleolytic processing by SbcC-SbcD and ExoI before chromosome replication can be completed...
December 5, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29207607/cyclin-a2-regulates-homologous-recombination-dna-repair-and-sensitivity-to-dna-damaging-agents-and-poly-adp-ribose-polymerase-parp-inhibitors-in-human-breast-cancer-cells
#13
Wei Wei Gu, Jie Lin, Xing Yu Hong
Defects in homologous recombination (HR) repair are found in breast cancers. Intriguingly, breast cancers with defective HR show increased sensitivity to DNA crosslinking agents and poly(ADP-ribose) polymerase (PARP) inhibitors. As such, genes that can affect HR functions have been of high interest in studies aiming to develop biomarkers for predicting response to treatment with these agents. Cyclin A2 is a key component of the core cell cycle machinery. However, whether cyclin A2 dysfunctions could cause HR defect and mediate sensitivity to DNA damaging agents remain unclear...
October 31, 2017: Oncotarget
https://www.readbyqxmd.com/read/29204698/fumarase-is-involved-in-dna-double-strand-break-resection-through-a-functional-interaction-with-sae2
#14
Michael Leshets, Dharanidharan Ramamurthy, Michael Lisby, Norbert Lehming, Ophry Pines
One of the most severe forms of DNA damage is the double-strand break (DSB). Failure to properly repair the damage can cause mutation, gross chromosomal rearrangements and lead to the development of cancer. In eukaryotes, homologous recombination (HR) and non-homologous end joining (NHEJ) are the main DSB repair pathways. Fumarase is a mitochondrial enzyme which functions in the tricarboxylic acid cycle. Intriguingly, the enzyme can be readily detected in the cytosolic compartment of all organisms examined, and we have shown that cytosolic fumarase participates in the DNA damage response towards DSBs...
December 4, 2017: Current Genetics
https://www.readbyqxmd.com/read/29180822/damage-induced-lncrnas-control-the-dna-damage-response-through-interaction-with-ddrnas-at-individual-double-strand-breaks
#15
Flavia Michelini, Sethuramasundaram Pitchiaya, Valerio Vitelli, Sheetal Sharma, Ubaldo Gioia, Fabio Pessina, Matteo Cabrini, Yejun Wang, Ilaria Capozzo, Fabio Iannelli, Valentina Matti, Sofia Francia, G V Shivashankar, Nils G Walter, Fabrizio d'Adda di Fagagna
The DNA damage response (DDR) preserves genomic integrity. Small non-coding RNAs termed DDRNAs are generated at DNA double-strand breaks (DSBs) and are critical for DDR activation. Here we show that active DDRNAs specifically localize to their damaged homologous genomic sites in a transcription-dependent manner. Following DNA damage, RNA polymerase II (RNAPII) binds to the MRE11-RAD50-NBS1 complex, is recruited to DSBs and synthesizes damage-induced long non-coding RNAs (dilncRNAs) from and towards DNA ends...
December 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/29170652/characteristic-eye-movements-in-ataxia-telangiectasia-like-disorder-an-explanatory-hypothesis
#16
Pamela Federighi, Stefano Ramat, Francesca Rosini, Elena Pretegiani, Antonio Federico, Alessandra Rufa
Objective: To investigate cerebellar dysfunctions and quantitatively characterize specific oculomotor changes in ataxia-telangiectasia-like disorder (ATLD), a rare autosomal recessive disease caused by mutations in the MRE11 gene. Additionally, to further elucidate the pathophysiology of cerebellar damage in the ataxia-telangiectasia (AT) spectrum disorders. Methods: Saccade dynamics, metrics, and visual fixation deficits were investigated in two Italian adult siblings with genetically confirmed ATLD...
2017: Frontiers in Neurology
https://www.readbyqxmd.com/read/29165875/4%C3%AE-hydroxywithanolide-e-selectively-induces-oxidative-dna-damage-for-selective-killing-of-oral-cancer-cells
#17
Jen-Yang Tang, Hurng-Wern Huang, Hui-Ru Wang, Ya-Ching Chan, Jo-Wen Haung, Chih-Wen Shu, Yang-Chang Wu, Hsueh-Wei Chang
Reactive oxygen species (ROS) induction had been previously reported in 4β-hydroxywithanolide (4βHWE)-induced selective killing of oral cancer cells, but the mechanism involving ROS and the DNA damage effect remain unclear. This study explores the role of ROS and oxidative DNA damage of 4βHWE in the selective killing of oral cancer cells. Changes in cell viability, morphology, ROS, DNA double strand break (DSB) signaling (γH2AX foci in immunofluorescence and DSB signaling in western blotting), and oxidative DNA damage (8-oxo-2'deoxyguanosine [8-oxodG]) were detected in 4βHWE-treated oral cancer (Ca9-22) and/or normal (HGF-1) cells...
November 22, 2017: Environmental Toxicology
https://www.readbyqxmd.com/read/29149348/mechanistic-insight-into-the-assembly-of-the-hera-nura-helicase-nuclease-dna-end-resection-complex
#18
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
#19
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
#20
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
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