Atsushi Shibata, Penny A Jeggo
In mammalian cells, the mediator protein, 53BP1, exerts distinct impacts on the repair of DNA double strand breaks (DSBs) depending on the setting, for example whether the DSBs arise at telomeres or during replication or class switch recombination. Here, we focus on two roles of 53BP1 in response to ionising radiation (IR)-induced DSBs (IR-DSBs). Canonical DNA non-homologous end-joining (c-NHEJ) is the major DSB repair pathway with homologous recombination (HR) contributing to DSB repair in S/G2 phase. ATM signalling promotes histone modifications and protein assembly in the DSB vicinity, which can be visualised as irradiation induced foci (IRIF)...
September 2020: DNA Repair
Andrea M Kaminski, Katarzyna Bebenek, Lars C Pedersen, Thomas A Kunkel
DNA polymerase μ is a Family X member that participates in repair of DNA double strand breaks (DSBs) by non-homologous end joining. Its role is to fill short gaps arising as intermediates in the process of V(D)J recombination and during processing of accidental double strand breaks. Pol μ is the only known template-dependent polymerase that can repair non-complementary DSBs with unpaired 3´primer termini. Here we review the unique properties of Pol μ that allow it to productively engage such a highly unstable substrate to generate a nick that can be sealed by DNA Ligase IV...
September 2020: DNA Repair
Alison Harrod, Karen A Lane, Jessica A Downs
Mammalian cells possess multiple closely related SWI/SNF chromatin remodelling complexes. These complexes have been implicated in the cellular response to DNA double strand breaks (DSBs). Evidence suggests that SWI/SNF complexes contribute to successful repair via both the homologous recombination and non-homologous end joining pathways. In addition, repressing transcription near DSBs is dependent on SWI/SNF activity. Understanding these roles is important because SWI/SNF complexes are frequently dysregulated in cancer, and DNA DSB repair defects have the potential to be therapeutically exploited...
September 2020: DNA Repair
Liang Song, Zizhi Tang, Changsheng Peng, Yueming Yang, Chang Guo, Danqing Wang, Liandi Guo, Jie Chen, Cong Liu
BACKGROUND: Loss of the genomic stability jeopardize genome stability and promote malignancies. A fraction of ovarian cancer (OvCa) arises from pathological mutations of DNA repair genes that result in highly mutagenic genomes. However, it remains elusive why the ovarian epithelial cells are particularly susceptible to the malfunction of genome surveillance system. METHODS: To explore the genotoxic responses in the unique context of microenvironment for ovarian epithelium that is periodically exposed to high-level steroid hormones, we examined estrogen-induced DNA damage by immunofluorescence in OvCa cell lines, animal and human samples...
October 21, 2020: BMC Cancer
Elisa Gobbini, Erika Casari, Chiara Vittoria Colombo, Diego Bonetti, Maria Pia Longhese
Homologous recombination is initiated by nucleolytic degradation (resection) of DNA double-strand breaks (DSBs). DSB resection is a two-step process in which an initial short-range step is catalyzed by the Mre11-Rad50-Xrs2 (MRX) complex and limited to the vicinity of the DSB end. Then the two long-range resection Exo1 and Dna2-Sgs1 nucleases extend the resected DNA tracts. How short-range resection is regulated and contributes to checkpoint activation remains to be determined. Here, we show that abrogation of long-range resection induces a checkpoint response that decreases DNA damage resistance...
October 20, 2020: Cell Reports
Sarah J Young, Marie Sebald, Rajvee Shah Punatar, Meghan Larin, Laura Masino, Monica C Rodrigo-Brenni, Chih-Chao Liang, Stephen C West
MutSα and MutSβ play important roles in DNA mismatch repair and are linked to inheritable cancers and degenerative disorders. Here, we show that MSH2 and MSH3, the two components of MutSβ, bind SLX4 protein, a scaffold for the assembly of the SLX1-SLX4-MUS81-EME1-XPF-ERCC1 (SMX) trinuclease complex. SMX promotes the resolution of Holliday junctions (HJs), which are intermediates in homologous recombinational repair. We find that MutSβ binds HJs and stimulates their resolution by SLX1-SLX4 or SMX in reactions dependent upon direct interactions between MutSβ and SLX4...
October 20, 2020: Cell Reports
Deepti Gurung, Robert M Blumenthal
Homologous recombination plays key roles in fundamental processes such as recovery from DNA damage and in bacterial horizontal gene transfer, yet there are still open questions about the distribution of recognized components of recombination machinery among bacteria and archaea. RecBCD helicase-nuclease plays a central role in recombination among Gammaproteobacteria like Escherichia coli ; while bacteria in other phyla, like the Firmicute Bacillus subtilis , use the related AddAB complex. The activity of at least some of these complexes is controlled by short DNA sequences called crossover hotspot instigator (Chi) sites...
October 21, 2020: Microbiology
Chung Ying Chan, Kel Vin Tan, Bart Cornelissen
Targeting of poly(ADP-ribose)polymerase (PARP) enzymes has emerged as an effective therapeutic strategy to selectively target cancer cells with deficiencies in homologous recombination (HR) signaling. Currently used to treat BRCA-mutated cancers, PARP inhibitors (PARPi) have demonstrated improved outcome in various cancer types as single agents. Ongoing efforts have seen the exploitation of PARPi combination therapies, boosting patient responses as a result of drug synergisms. Despite great successes using PARPi therapy, selecting those patients who will benefit from single agent or combination therapy remains one of the major challenges...
October 20, 2020: Clinical Cancer Research
Bijoya Karmakar, Bodhisattwa Saha, Kuladip Jana, Swati Gupta Bhattacharya
Aspergillus terreus is an allergenic fungus in addition to causing infections in both humans and plants. However, the allergens in this fungus are still unknown, limiting the development of diagnostic and therapeutic strategies. We used a proteomic approach to search for allergens, identifying sixteen allergens based on two-dimensional immunoblotting with A. terreus susceptible patient sera. We further characterized triosephosphate isomerase (Asp t 36), one of the dominant immunoglobulin E (IgE)-reactive proteins...
October 20, 2020: Journal of Biological Chemistry
Ram Karan, Sam Mathew, Reyhan Muhammad, Didier B Bautista, Malvina Vogler, Jorg Eppinger, Romina Oliva, Luigi Cavallo, Stefan T Arold, Magnus Rueping
The haloarchaeon Halorubrum lacusprofundi is among the few polyextremophilic organisms capable of surviving in one of the most extreme aquatic environments on Earth, the Deep Lake of Antarctica (-18 °C to +11.5 °C and 21-28%, w/v salt content). Hence, H. lacusprofundi has been proposed as a model for biotechnology and astrobiology to investigate potential life beyond Earth. To understand the mechanisms that allow proteins to adapt to both salinity and cold, we structurally (including X-ray crystallography and molecular dynamics simulations) and functionally characterized the β-galactosidase from H...
October 16, 2020: Microorganisms
Mohak Sharda, Anjana Badrinarayanan, Aswin Sai Narain Seshasayee
DNA double-strand breaks (DSBs) are a threat to genome stability. In all domains of life, DSBs are faithfully fixed via homologous recombination. Recombination requires the presence of an uncut copy of duplex DNA which is used as a template for repair. Alternatively, in the absence of a template, cells utilize error-prone Non-homologous end joining (NHEJ). Although ubiquitously found in eukaryotes, NHEJ is not universally present in bacteria. It is unclear as to why many prokaryotes lack this pathway. Towards understanding what could have led to the current distribution of bacterial NHEJ, we carried out comparative genomics and phylogenetic analysis across ∼6000 genomes...
October 20, 2020: Genome Biology and Evolution
Steffen Hirsch, Laura Gieldon, Christian Sutter, Nicola Dikow, Christian P Schaaf
Pathogenic variants in the BRCA1 and BRCA2 genes are well known causes of hereditary breast and ovarian cancer. Other genes involved in the homologous recombination pathway can also be associated with increased probability of cancer development, for example, breast and ovarian cancer, prostate and pancreatic cancer, colorectal cancer and even childhood tumors like medulloblastoma. Traditionally, patients and families likely to harbor a genetic predisposition have been identified using personal and family history...
October 20, 2020: Genes, Chromosomes & Cancer
Hanae Utsunomiya, Nozomi Saiki, Hayato Kadoguchi, Masaya Fukudome, Satomi Hashimoto, Mami Ueda, Katsuaki Takechi, Hiroyoshi Takano
Homologous genes for the peptidoglycan precursor flippase MurJ, and peptidoglycan hydrolases: lytic transglycosylase MltB, and DD-carboxypeptidase VanY are required for chloroplast division in the moss Physcomitrella patens. The moss Physcomitrella patens is used as a model plant to study plastid peptidoglycan biosynthesis. In bacteria, MurJ flippase transports peptidoglycan precursors from the cytoplasm to the periplasm. In this study, we identified a MurJ homolog (PpMurJ) in the P. patens genome. Bacteria employ peptidoglycan degradation and recycling pathways for cell division...
October 19, 2020: Plant Molecular Biology
Isidoro Feliciello, Željka Pezer, Dušan Kordiš, Branka Bruvo Mađarić, Đurđica Ugarković
Major human alpha satellite DNA repeats are preferentially assembled within (peri)centromeric regions but are also dispersed within euchromatin in the form of clustered or short single repeat arrays. To study the evolutionary history of single euchromatic human alpha satellite repeats (AR) we analysed their orthologous loci across the primate genomes. The continuous insertion of euchromatic ARs throughout the evolutionary history of primates starting with the ancestors of Simiformes (45-60 Myr ago) and continuing up to the ancestors of Homo is revealed...
October 20, 2020: Genome Biology and Evolution
Douglas I Lin, Jonathan K Killian, Jeffrey M Venstrom, Shakti H Ramkissoon, Jeffrey S Ross, Julia A Elvin
Malignant Brenner tumor is a rare primary ovarian carcinoma subtype that may present diagnostic and therapeutic conundrums. Here, we characterize the genomics of 11 malignant Brenner tumors, which represented 0.1% of 14,153 clinically advanced ovarian carcinomas submitted for genomic profiling during the course of clinical care. At the time of molecular profiling, there was no evidence of a primary urothelial carcinoma of the urinary tract in any case. Cases with transitional-like morphologic features in the setting of variant ovarian serous or endometrioid carcinoma morphology were excluded from the final cohort...
October 19, 2020: Modern Pathology
Joonho Suh, Yun-Sil Lee
Growth differentiation factor 11 (GDF11) and myostatin (MSTN) are closely related TGFβ family members that are often believed to serve similar functions due to their high homology. However, genetic studies in animals provide clear evidence that they perform distinct roles. While the loss of Mstn leads to hypermuscularity, the deletion of Gdf11 results in abnormal skeletal patterning and organ development. The perinatal lethality of Gdf11-null mice, which contrasts with the long-term viability of Mstn-null mice, has led most research to focus on utilizing recombinant GDF11 proteins to investigate the postnatal functions of GDF11...
October 19, 2020: Experimental & Molecular Medicine
Ju-Li Jing, Ting Zhang, Yu-Hsin Kao, Tzu-Han Huang, Chung-Ju Rachel Wang, Yan He
The meiotic TopoVI B subunit (MTopVIB) plays an essential role in DSB formation in mouse, Arabidopsis (Arabidopsis thaliana) and rice (Oryza sativa), and recent work reveals rice MTopVIB also plays an unexpected role in meiotic bipolar spindle assembly, highlighting multiple functions of MTopVIB during rice meiosis. In this work, we characterized the meiotic TopVIB in maize (Zea mays; ZmMTOPVIB). The ZmmtopVIB mutant plants exhibited normal vegetative growth but male and female sterility. Meiotic DSB formation was abolished in mutant meiocytes...
October 19, 2020: Plant Physiology
Kodsara Ramachandra Kiran, Vishwanath Bhat Deepika, Puthanvila Surendrababu Swathy, Keshava Prasad, Shama Prasada Kabekkodu, Thokur Sreepathy Murali, Kapaettu Satyamoorthy, Annamalai Muthusamy
Reactive oxygen species (ROS) generated during rehydration of seeds is a major source of cellular damage. Successful germination depends on maintaining the oxidative window and ability of the cells to repair the DNA damage accumulated during seed developmental process, maturational drying, and germination. We explored the role of DNA damage, repair, cell cycle progression and antioxidant machinery in germination of seeds of Solanum melongena L. primed with 0, 320, 640 and 1200 mM sodium chloride (NaCl). The expression of antioxidant genes such as ascorbate peroxidase (APX), superoxide dismutase (SOD), catalase2 (CAT2), and glutathione reductase (GR) was upregulated to maintain the oxidative window required for germination in seeds treated with 320 mM NaCl...
October 10, 2020: Journal of Photochemistry and Photobiology. B, Biology
Nathan Palmer, S Zakiah A Talib, Priti Singh, Christine M F Goh, Kui Liu, John C Schimenti, Philipp Kaldis
Genetic diversity in offspring is induced by meiotic recombination, which is initiated between homologs at >200 sites originating from meiotic double-strand breaks (DSBs). Of this initial pool, only 1-2 DSBs per homolog pair will be designated to form meiotic crossovers (COs), where reciprocal genetic exchange occurs between parental chromosomes. Cyclin-dependent kinase 2 (CDK2) is known to localize to so-called "late recombination nodules" (LRNs) marking incipient CO sites. However, the role of CDK2 kinase activity in the process of CO formation remains uncertain...
October 19, 2020: PLoS Biology
Jong-Soo Kang, Hong-Rui Zhang, Ya-Rong Wang, Si-Qi Liang, Zhi-Yuan Mao, Xian-Chun Zhang, Qiao-Ping Xiang
Plastids and mitochondria are endosymbiotic organelles that store genetic information. The genomes of these organelles generally exhibit contrasting patterns regarding genome architecture and genetic content. However, they have similar genetic features in Selaginellaceae, and little is known about what causes parallel evolution. Here, we document the multipartite plastid genomes (plastomes) and the highly divergent mitochondrial genomes (mitogenomes) from spikemoss obtained by combining short- and long-reads...
October 19, 2020: Plant Journal
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