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Thomas E Bass, Jessica W Luzwick, Gina Kavanaugh, Clinton Carroll, Huzefa Dungrawala, Gloria G Glick, Michael D Feldkamp, Reid Putney, Walter J Chazin, David Cortez
The ATR checkpoint kinase coordinates cellular responses to DNA replication stress. Budding yeast contain three activators of Mec1 (the ATR orthologue); however, only TOPBP1 is known to activate ATR in vertebrates. We identified ETAA1 as a replication stress response protein in two proteomic screens. ETAA1-deficient cells accumulate double-strand breaks, sister chromatid exchanges, and other hallmarks of genome instability. They are also hypersensitive to replication stress and have increased frequencies of replication fork collapse...
October 10, 2016: Nature Cell Biology
Yasuko Kamisugi, John W Whitaker, Andrew C Cuming
The model bryophyte Physcomitrella patens is unique among plants in supporting the generation of mutant alleles by facile homologous recombination-mediated gene targeting (GT). Reasoning that targeted transgene integration occurs through the capture of transforming DNA by the homology-dependent pathway for DNA double-strand break (DNA-DSB) repair, we analysed the genome-wide transcriptomic response to bleomycin-induced DNA damage and generated mutants in candidate DNA repair genes. Massively parallel (Illumina) cDNA sequencing identified potential participants in gene targeting...
2016: PloS One
Qing Hu, Ding Tang, Hongjun Wang, Yi Shen, Xiaojun Chen, Jianhui Ji, Guijie Du, Yafei Li, Zhukuan Cheng
During meiosis, programmed double-strand breaks (DSBs) are generated to initiate homologous recombination, which is crucial for faithful chromosome segregation. In yeast, Radiation sensitive1 (RAD1) acts together with Radiation sensitive9 (RAD9) and Hydroxyurea sensitive1 (HUS1) to facilitate meiotic recombination via cell-cycle checkpoint control. However, little is known about the meiotic functions of these proteins in higher eukaryotes. Here, we characterized a RAD1 homolog in rice (Oryza sativa) and obtained evidence that O...
October 2016: Plant Physiology
Yasunori Fukumoto, Masayoshi Ikeuchi, Yuji Nakayama, Naoto Yamaguchi
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...
September 2, 2016: Biochemical and Biophysical Research Communications
Jeziel D Damasceno, Ricardo Obonaga, Elaine V Santos, Alan Scott, Richard McCulloch, Luiz R O Tosi
The Rad9-Rad1-Hus1 (9-1-1) complex is a key component in the coordination of DNA damage sensing, cell cycle progression and DNA repair pathways in eukaryotic cells. This PCNA-related trimer is loaded onto RPA-coated single stranded DNA and interacts with ATR kinase to mediate effective checkpoint signaling to halt the cell cycle and to promote DNA repair. Beyond these core activities, mounting evidence suggests that a broader range of functions can be provided by 9-1-1 structural diversification. The protozoan parasite Leishmania is an early-branching eukaryote with a remarkably plastic genome, which hints at peculiar genome maintenance mechanisms...
September 2016: Molecular Microbiology
Sanket Awate, Arrigo De Benedetti
BACKGROUND: The Tousled like kinase 1B (TLK1B) is critical for DNA repair and survival of cells. Upon DNA damage, Chk1 phosphorylates TLK1B at S457 leading to its transient inhibition. Once TLK1B regains its kinase activity it phosphorylates Rad9 at S328. In this work we investigated the significance of this mechanism by overexpressing mutant TLK1B in which the inhibitory phosphorylation site was eliminated. RESULTS AND DISCUSSION: These cells expressing TLK1B resistant to DNA damage showed constitutive phosphorylation of Rad9 S328 that occurred even in the presence of hydroxyurea (HU), and this resulted in a delayed checkpoint recovery...
2016: BMC Molecular Biology
Gisella Figlioli, Rossella Elisei, Cristina Romei, Ombretta Melaiu, Monica Cipollini, Franco Bambi, Bowang Chen, Aleksandra Köhler, Alfonso Cristaudo, Kari Hemminki, Federica Gemignani, Asta Försti, Stefano Landi
BACKGROUND: Linkage analyses and association studies suggested that inherited genetic variations play a role in the development of differentiated thyroid carcinoma (DTC). METHODS: We combined the results from a genome-wide association study (GWAS) performed by our group and from published studies on DTC. With a first approach, we evaluated whether a SNP published as associated with the risk of DTC could replicate in our GWAS (using FDR as adjustment for multiple comparisons)...
April 2016: Cancer Epidemiology, Biomarkers & Prevention
X-J Peng, S-J Liu, C-M Bao, Y-Z Liu, H-W Xie, Y-H Cai, B-M Li, H-Y Hang, X Ding
Genotoxic stress activates checkpoint signaling pathways that activate the checkpoint kinases ATM and ATR, halt cell cycle progression, and promote DNA repair. A number of proteins act in concert with ATR to phosphorylate Chk1, including RAD17, the RAD9-RAD1-HUS1 complex, ATR/ATRIP and TopBp1. However, how these proteins involved act in concert with one another to propagate and maintain the checkpoint response is not well understood. Here, we reported that upregulation of RAD9 protein increased the quantity of ATRIP, suggesting that RAD9 activation will induce more efficient accumulation of ATRIP in vivo...
2015: Cellular and Molecular Biology
Ye Zhao, Xiaoyan Ma, Jun Wang, Shaopeng Chen, Hang Yuan, An Xu, Haiying Hang, Lijun Wu
Previously reported studies have demonstrated the involvement of p21(Waf1/CIP1) in radiation-induced bystander effects (RIBE). Mouse embryonic fibroblasts (MEFs) lacking Hus1 fail to proliferate in vitro, but inactivation of p21 allows for the continued growth of Hus1-deficient cells, indicating the close connection between p21 and Hus1 cells. In this study, wild-type MEFs, Hus1(+/+)p21(-/-) MEFs and p21(-/-)Hus1(-/-) MEFs were used in a series of radiation-induced bystander effect experiments, the roles of p21 and Hus1 in the induction and transmission of radiation-induced damage signals were investigated...
December 2015: Radiation Research
Mikhail Shaposhnikov, Ekaterina Proshkina, Lyubov Shilova, Alex Zhavoronkov, Alexey Moskalev
DNA repair declines with age and correlates with longevity in many animal species. In this study, we investigated the effects of GAL4-induced overexpression of genes implicated in DNA repair on lifespan and resistance to stress factors in Drosophila melanogaster. Stress factors included hyperthermia, oxidative stress, and starvation. Overexpression was either constitutive or conditional and either ubiquitous or tissue-specific (nervous system). Overexpressed genes included those involved in recognition of DNA damage (homologs of HUS1, CHK2), nucleotide and base excision repair (homologs of XPF, XPC and AP-endonuclease-1), and repair of double-stranded DNA breaks (homologs of BRCA2, XRCC3, KU80 and WRNexo)...
2015: Scientific Reports
Megan K Brinkmeyer, Sheila S David
MUTYH is a base excision repair (BER) enzyme that prevents mutations in DNA associated with 8-oxoguanine (OG) by catalyzing the removal of adenine from inappropriately formed OG:A base-pairs. Germline mutations in the MUTYH gene are linked to colorectal polyposis and a high risk of colorectal cancer, a syndrome referred to as MUTYH-associated polyposis (MAP). There are over 300 different MUTYH mutations associated with MAP and a large fraction of these gene changes code for missense MUTYH variants. Herein, the adenine glycosylase activity, mismatch recognition properties, and interaction with relevant protein partners of human MUTYH and five MAP variants (R295C, P281L, Q324H, P502L, and R520Q) were examined...
October 2015: DNA Repair
Eva Mejia-Ramirez, Oliver Limbo, Petra Langerak, Paul Russell
Phosphorylation of histone H2AX by ATM and ATR establishes a chromatin recruitment platform for DNA damage response proteins. Phospho-H2AX (γH2AX) has been most intensively studied in the context of DNA double-strand breaks caused by exogenous clastogens, but recent studies suggest that DNA replication stress also triggers formation of γH2A (ortholog of γH2AX) in Schizosaccharomyces pombe. Here, a focused genetic screen in fission yeast reveals that γH2A is critical when there are defects in Replication Factor C (RFC), which loads proliferating cell nuclear antigen (PCNA) clamp onto duplex DNA...
September 2015: PLoS Genetics
Se Hee Han, Soo-Hyun Hahm, An Hue Vy Tran, Ji Hyung Chung, Myoung-Ki Hong, Hyun-Dong Paik, Key-Sun Kim, Ye Sun Han
BACKGROUND: Human DNA topoisomerase II-binding protein 1 (hTopBP1) plays an important role in DNA replication and the DNA damage checkpoint pathway. The human mutY homolog (hMYH) is a base excision repair DNA glycosylase that excises adenines or 2-hydroxyadenines that are mispaired with guanine or 7,8-dihydro-8-oxoguanine (8-oxoG). hTopBP1 and hMYH were involved in ATR-mediated Chk1 activation, moreover, both of them were associated with ATR and hRad9 which known as checkpoint-involved proteins...
2015: Cell & Bioscience
Lihua Song, Lijun Ma, Fengsong Cong, Xiuhua Shen, Pu Jing, Xiong Ying, Haiyue Zhou, Jing Jiang, Yongye Fu, Hongli Yan
Radiation induced normal tissue damage is the most important limitation for the delivery of a high potentially curative radiation dose. Genistein (GEN), one of the main soy isoflavone components, has drawn wide attention for its bioactivity in alleviating radiation damage. However, the effects and molecular mechanisms underlying the radioprotective effects of GEN remain unclear. In the present study, we showed that low concentration of GEN (1.5 µM) protected L-02 cells against radiation damage via inhibition of apoptosis, alleviation of DNA damage and chromosome aberration, down-regulation of GRP78 and up-regulation of HERP, HUS1 and hHR23A...
September 28, 2015: Cancer Letters
Yukimasa Takeishi, Rie Iwaya-Omi, Eiji Ohashi, Toshiki Tsurimoto
The human checkpoint clamp Rad9-Hus1-Rad1 (9-1-1) is loaded onto chromatin by its loader complex, Rad17-RFC, following DNA damage. The 120-amino acid (aa) stretch of the Rad9 C terminus (C-tail) is unstructured and projects from the core ring structure (CRS). Recent studies showed that 9-1-1 and CRS bind DNA independently of Rad17-RFC. The DNA-binding affinity of mutant 9(ΔC)-1-1, which lacked the Rad9 C-tail, was much higher than that of wild-type 9-1-1, suggesting that 9-1-1 has intrinsic DNA binding activity that manifests in the absence of the C-tail...
August 7, 2015: Journal of Biological Chemistry
Bor-Jang Hwang, Jin Jin, Ying Gao, Guoli Shi, Amrita Madabushi, Austin Yan, Xin Guan, Michal Zalzman, Satoshi Nakajima, Li Lan, A-Lien Lu
BACKGROUND: SIRT6, a member of the NAD(+)-dependent histone/protein deacetylase family, regulates genomic stability, metabolism, and lifespan. MYH glycosylase and APE1 are two base excision repair (BER) enzymes involved in mutation avoidance from oxidative DNA damage. Rad9-Rad1-Hus1 (9-1-1) checkpoint clamp promotes cell cycle checkpoint signaling and DNA repair. BER is coordinated with the checkpoint machinery and requires chromatin remodeling for efficient repair. SIRT6 is involved in DNA double-strand break repair and has been implicated in BER...
2015: BMC Molecular Biology
Bor-Jang Hwang, Jin Jin, Randall Gunther, Amrita Madabushi, Guoli Shi, Gerald M Wilson, A-Lien Lu
Cell cycle checkpoints provide surveillance mechanisms to activate the DNA damage response, thus preserving genomic integrity. The heterotrimeric Rad9-Rad1-Hus1 (9-1-1) clamp is a DNA damage response sensor and can be loaded onto DNA. 9-1-1 is involved in base excision repair (BER) by interacting with nearly every enzyme in BER. Here, we show that individual 9-1-1 components play distinct roles in BER directed by MYH DNA glycosylase. Analyses of Hus1 deletion mutants revealed that the interdomain connecting loop (residues 134-155) is a key determinant of MYH binding...
July 2015: DNA Repair
Ananya Kar, Manpreet Kaur, Tanushree Ghosh, Md Muntaz Khan, Aparna Sharma, Ritu Shekhar, Akhil Varshney, Sandeep Saxena
The primary eukaryotic single-stranded DNA-binding protein, Replication protein A (RPA), binds to single-stranded DNA at the sites of DNA damage and recruits the apical checkpoint kinase, ATR via its partner protein, ATRIP. It has been demonstrated that absence of RPA incapacitates the ATR-mediated checkpoint response. We report that in the absence of RPA, human single-stranded DNA-binding protein 1 (hSSB1) and its partner protein INTS3 form sub-nuclear foci, associate with the ATR-ATRIP complex and recruit it to the sites of genomic stress...
May 26, 2015: Nucleic Acids Research
G Balmus, P X Lim, A Oswald, K R Hume, A Cassano, J Pierre, A Hill, W Huang, A August, T Stokol, T Southard, R S Weiss
Cells are under constant attack from genotoxins and rely on a multifaceted DNA damage response (DDR) network to maintain genomic integrity. Central to the DDR are the ATM and ATR kinases, which respond primarily to double-strand DNA breaks (DSBs) and replication stress, respectively. Optimal ATR signaling requires the RAD9A-RAD1-HUS1 (9-1-1) complex, a toroidal clamp that is loaded at damage sites and scaffolds signaling and repair factors. Whereas complete ATR pathway inactivation causes embryonic lethality, partial Hus1 impairment has been accomplished in adult mice using hypomorphic (Hus1(neo)) and null (Hus1(Δ1)) Hus1 alleles, and here we use this system to define the tissue- and cell type-specific actions of the HUS1-mediated DDR in vivo...
February 4, 2016: Oncogene
Pei Xin Lim, Darshil R Patel, Kelsey E Poisson, Manpreet Basuita, Charlton Tsai, Amy M Lyndaker, Bor-Jang Hwang, A-Lien Lu, Robert S Weiss
The RAD9A-HUS1-RAD1 (9-1-1) complex is a heterotrimeric clamp that promotes checkpoint signaling and repair at DNA damage sites. In this study, we elucidated HUS1 functional residues that drive clamp assembly, DNA interactions, and downstream effector functions. First, we mapped a HUS1-RAD9A interface residue that was critical for 9-1-1 assembly and DNA loading. Next, we identified multiple positively charged residues in the inner ring of HUS1 that were crucial for genotoxin-induced 9-1-1 chromatin localization and ATR signaling...
June 12, 2015: Journal of Biological Chemistry
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