Anthony T. Tubbs
Washington University in St. Louis
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Publication
Featured researches published by Anthony T. Tubbs.
Cell | 2013
Elsa Callen; Michela Di Virgilio; Michael J. Kruhlak; Maria Nieto-Soler; Nancy Wong; Hua Tang Chen; Robert B. Faryabi; Federica Polato; Margarida Almeida Santos; Linda M. Starnes; Duane R. Wesemann; Ji-Eun Lee; Anthony T. Tubbs; Barry P. Sleckman; Jeremy A. Daniel; Kai Ge; Frederick W. Alt; Oscar Fernandez-Capetillo; Michel C. Nussenzweig; André Nussenzweig
The DNA damage response (DDR) protein 53BP1 protects DNA ends from excessive resection in G1, and thereby favors repair by nonhomologous end-joining (NHEJ) as opposed to homologous recombination (HR). During S phase, BRCA1 antagonizes 53BP1 to promote HR. The pro-NHEJ and antirecombinase functions of 53BP1 are mediated in part by RIF1, the only known factor that requires 53BP1 phosphorylation for its recruitment to double-strand breaks (DSBs). Here, we show that a 53BP1 phosphomutant, 53BP18A, comprising alanine substitutions of the eight most N-terminal S/TQ phosphorylation sites, mimics 53BP1 deficiency by restoring genome stability in BRCA1-deficient cells yet behaves like wild-type 53BP1 with respect to immunoglobulin class switch recombination (CSR). 53BP18A recruits RIF1 but fails to recruit the DDR protein PTIP to DSBs, and disruption of PTIP phenocopies 53BP18A. We conclude that 53BP1 promotes productive CSR and suppresses mutagenic DNA repair through distinct phosphodependent interactions with RIF1 and PTIP.
Nature | 2011
Beth A. Helmink; Anthony T. Tubbs; Yair Dorsett; Jeffrey J. Bednarski; Laura M. Walker; Zhihui Feng; Girdhar G. Sharma; Peter J. McKinnon; Junran Zhang; Craig H. Bassing; Barry P. Sleckman
DNA double-strand breaks (DSBs) are generated by the recombination activating gene (RAG) endonuclease in all developing lymphocytes as they assemble antigen receptor genes. DNA cleavage by RAG occurs only at the G1 phase of the cell cycle and generates two hairpin-sealed DNA (coding) ends that require nucleolytic opening before their repair by classical non-homologous end-joining (NHEJ). Although there are several cellular nucleases that could perform this function, only the Artemis nuclease is able to do so efficiently. Here, in vivo, we show that in murine cells the histone protein H2AX prevents nucleases other than Artemis from processing hairpin-sealed coding ends; in the absence of H2AX, CtIP can efficiently promote the hairpin opening and resection of DNA ends generated by RAG cleavage. This CtIP-mediated resection is inhibited by γ-H2AX and by MDC-1 (mediator of DNA damage checkpoint 1), which binds to γ-H2AX in chromatin flanking DNA DSBs. Moreover, the ataxia telangiectasia mutated (ATM) kinase activates antagonistic pathways that modulate this resection. CtIP DNA end resection activity is normally limited to cells at post-replicative stages of the cell cycle, in which it is essential for homology-mediated repair. In G1-phase lymphocytes, DNA ends that are processed by CtIP are not efficiently joined by classical NHEJ and the joints that do form frequently use micro-homologies and show significant chromosomal deletions. Thus, H2AX preserves the structural integrity of broken DNA ends in G1-phase lymphocytes, thereby preventing these DNA ends from accessing repair pathways that promote genomic instability.DNA double-strand breaks (DSBs) are generated by the recombination activating gene (RAG) endonuclease in all developing lymphocytes as they assemble antigen receptor genes. DNA cleavage by RAG occurs only at the G1 phase of the cell cycle and generates two hairpin-sealed DNA (coding) ends that require nucleolytic opening before their repair by classical non-homologous end-joining (NHEJ). Although there are several cellular nucleases that could perform this function, only the Artemis nuclease is able to do so efficiently. Here, in vivo, we show that in murine cells the histone protein H2AX prevents nucleases other than Artemis from processing hairpin-sealed coding ends; in the absence of H2AX, CtIP can efficiently promote the hairpin opening and resection of DNA ends generated by RAG cleavage. This CtIP-mediated resection is inhibited by γ-H2AX and by MDC-1 (mediator of DNA damage checkpoint 1), which binds to γ-H2AX in chromatin flanking DNA DSBs. Moreover, the ataxia telangiectasia mutated (ATM) kinase activates antagonistic pathways that modulate this resection. CtIP DNA end resection activity is normally limited to cells at post-replicative stages of the cell cycle, in which it is essential for homology-mediated repair. In G1-phase lymphocytes, DNA ends that are processed by CtIP are not efficiently joined by classical NHEJ and the joints that do form frequently use micro-homologies and show significant chromosomal deletions. Thus, H2AX preserves the structural integrity of broken DNA ends in G1-phase lymphocytes, thereby preventing these DNA ends from accessing repair pathways that promote genomic instability.
Cell | 2017
Anthony T. Tubbs; André Nussenzweig
Genome instability, defined as higher than normal rates of mutation, is a double-edged sword. As a source of genetic diversity and natural selection, mutations are beneficial for evolution. On the other hand, genomic instability can have catastrophic consequences for age-related diseases such as cancer. Mutations arise either from inactivation of DNA repair pathways or in a repair-competent background due to genotoxic stress from celluar processes such as transcription and replication that overwhelm high-fidelity DNA repair. Here, we review recent studies that shed light on endogenous sources of mutation and epigenomic features that promote genomic instability during cancer evolution.
Nature Communications | 2016
Xia Ding; Arnab Ray Chaudhuri; Elsa Callen; Yan Pang; Kajal Biswas; Kimberly D. Klarmann; Betty K. Martin; Sandra Burkett; Linda Cleveland; Stacey Stauffer; Teresa Sullivan; Aashish Dewan; Hanna Marks; Anthony T. Tubbs; Nancy Wong; Eugen Buehler; Keiko Akagi; Scott E. Martin; Jonathan R. Keller; André Nussenzweig; Shyam K. Sharan
Poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) olaparib has been approved for treatment of advanced ovarian cancer associated with BRCA1 and BRCA2 mutations. BRCA1- and BRCA2-mutated cells, which are homologous recombination (HR) deficient, are hypersensitive to PARPi through the mechanism of synthetic lethality. Here we examine the effect of PARPi on HR-proficient cells. Olaparib pretreatment, PARP1 knockdown or Parp1 heterozygosity of Brca2cko/ko mouse embryonic stem cells (mESCs), carrying a null (ko) and a conditional (cko) allele of Brca2, results in viable Brca2ko/ko cells. PARP1 deficiency does not restore HR in Brca2ko/ko cells, but protects stalled replication forks from MRE11-mediated degradation through its impaired recruitment. The functional consequence of Parp1 heterozygosity on BRCA2 loss is demonstrated by a significant increase in tumorigenesis in Brca2cko/cko mice. Thus, while olaparib efficiently kills BRCA2-deficient cells, we demonstrate that it can also contribute to the synthetic viability if PARP is inhibited before BRCA2 loss.
Journal of Experimental Medicine | 2013
Natalie C. Steinel; Baeck-Seung Lee; Anthony T. Tubbs; Jeffrey J. Bednarski; Emily Schulte; Katherine S. Yang-Iott; David G. Schatz; Barry P. Sleckman; Craig H. Bassing
DNA double-strand breaks induced during Igκ recombination signal through ATM to suppress the initiation of additional Vκ-to-Jκ rearrangements.
Molecular and Cellular Biology | 2014
Anthony T. Tubbs; Yair Dorsett; Elizabeth Chan; Beth A. Helmink; Baeck-Seung Lee; Putzer Hung; Rosmy George; Andrea L. Bredemeyer; Anuradha Mittal; Rohit V. Pappu; Dipanjan Chowdhury; Nima Mosammaparast; Michael S. Krangel; Barry P. Sleckman
ABSTRACT The resection of broken DNA ends is required for DNA double-strand break (DSB) repair by homologous recombination (HR) but can inhibit normal repair by nonhomologous end joining (NHEJ), the main DSB repair pathway in G1-phase cells. Antigen receptor gene assembly proceeds through DNA DSB intermediates generated in G1-phase lymphocytes by the RAG endonuclease. These DSBs activate ATM, which phosphorylates H2AX, forming γ-H2AX in flanking chromatin. γ-H2AX prevents CtIP from initiating resection of RAG DSBs. Whether there are additional proteins required to promote resection of these DNA ends is not known. KRAB-associated protein 1 (KAP-1) (TRIM28) is a transcriptional repressor that modulates chromatin structure and has been implicated in the repair of DNA DSBs in heterochromatin. Here, we show that in murine G1-phase lymphocytes, KAP-1 promotes resection of DSBs that are not protected by H2AX and its downstream effector 53BP1. In these murine cells, KAP-1 activity in DNA end resection is attenuated by a single-amino-acid change that reflects a KAP-1 polymorphism between primates and other mammalian species. These findings establish KAP-1 as a component of the machinery that can resect DNA ends in G1-phase cells and suggest that there may be species-specific features to this activity.
eLife | 2017
Abigail J. Morales; Javier A. Carrero; Putzer J. Hung; Anthony T. Tubbs; Jared M Andrews; Brian T. Edelson; Boris Calderon; Cynthia L. Innes; Richard S. Paules; Jacqueline E. Payton; Barry P. Sleckman
Macrophages produce genotoxic agents, such as reactive oxygen and nitrogen species, that kill invading pathogens. Here we show that these agents activate the DNA damage response (DDR) kinases ATM and DNA-PKcs through the generation of double stranded breaks (DSBs) in murine macrophage genomic DNA. In contrast to other cell types, initiation of this DDR depends on signaling from the type I interferon receptor. Once activated, ATM and DNA-PKcs regulate a genetic program with diverse immune functions and promote inflammasome activation and the production of IL-1β and IL-18. Indeed, following infection with Listeria monocytogenes, DNA-PKcs-deficient murine macrophages produce reduced levels of IL-18 and are unable to optimally stimulate IFN-γ production by NK cells. Thus, genomic DNA DSBs act as signaling intermediates in murine macrophages, regulating innate immune responses through the initiation of a type I IFN-dependent DDR. DOI: http://dx.doi.org/10.7554/eLife.24655.001
Cell | 2018
Colleen T. Skau; Robert S. Fischer; Pinar S. Gurel; Hawa Racine Thiam; Anthony T. Tubbs; Michelle A. Baird; Michael W. Davidson; Matthieu Piel; Gregory M. Alushin; André Nussenzweig; Patricia S. Steeg; Clare M. Waterman
Our study reported that the formin-family actin nucleator FMN2 has a critical role in generating a perinuclear actin/FA system that protects the nucleus and DNA from damage, facilitating cell survival during confined cell migration associated with cancer metastasis. Shortly following publication, a lab with whom we had shared reagents noticed that cell lines that were supposed to be stably expressing GFP-FMN2 were not. We subsequently found that a western blot in the paper had been inappropriately manipulated and that multiple cell lines were not as reported. When we constructed and validated new cell lines and reagents, our attempts to reproduce critical results in the paper were unsuccessful. Based on an assessment by the NIH, analysis by the Department of Health and Human Services Office of Research Integrity (ORI), and Dr. Skau’s admission, the ORI found that the first author Colleen Skau engaged in research misconduct by fabrication and falsification of results reported in Figures 2, 3, 5, 6, 7, S2, S4, S5, S6, and S7, including reporting data that did not originate from experimental observations, selectively including and omitting data points, selectively omitting images and conditions from analyses, falsifying the quantitation of data including statistical analyses, and falsifying a western blot. We are therefore retracting the paper, and we apologize for the inconvenience we have caused.
Cell Cycle | 2014
Anthony T. Tubbs; Barry P. Sleckman
Genomic instability is a hallmark of cancer that can arise through the aberrant repair of DNA double strand breaks (DSBs) leading to the formation of chromosomal translocations, deletions, and inversions.1 Although these lesions are often functionally inert they can have pathologic consequences by altering gene expression or encoding novel fusion proteins that participate in tumorigenesis by driving cellular transformation or improving tumor cell fitness. These chromosomal aberrations occur at increased frequency in cells with inherited or somatically acquired mutations that compromise DNA DSB repair.
Molecular Cell | 2014
Nodar Makharashvili; Anthony T. Tubbs; Soo Hyun Yang; Hailong Wang; Olivia Barton; Yi Zhou; Rajashree A. Deshpande; Ji-Hoon Lee; Markus Löbrich; Barry P. Sleckman; Xiaohua Wu; Tanya T. Paull