John Tainer

John Tainer
University of Texas MD Anderson Cancer Center | MD Anderson · Departments of Molecular and Cellular Oncology and Cancer Biology

Ph.D.
Seeking students and fellows for predictive mechanistic research on DNA damage and immune responses for cancer impacts

About

712
Publications
278,121
Reads
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51,765
Citations
Introduction
We aim to define molecular mechanisms for 1) genome stability and instability in cancer, 2) connected DNA damage and immune responses, and 3) cancer targets and biomarkers. Our results seek to predict and control outcomes for disease and biotechnology. We integrate solution X-ray scattering (SAXS), crystallography, and EM data with computation and imaging to reveal predictive dynamic assemblies tested by mutations and chemical inhibitors for biology and therapy – https://sibyls.als.lbl.gov/
Additional affiliations
March 2015 - present
University of Texas MD Anderson Cancer Center
Position
  • Professor (Full)
January 2002 - present
Lawrence Berkeley National Laboratory
Position
  • Senior Scientist
January 1992 - present
The Scripps Research Institute
Position
  • Professor (Full)
Education
September 1976 - March 1982
Duke University
Field of study
  • Biochemistry

Publications

Publications (712)
Article
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Poly(ADP-ribose)ylation (PARylation) by PAR polymerase 1 (PARP1) and PARylation removal by poly(ADP-ribose) glycohydrolase (PARG) critically regulate DNA damage responses; yet, conflicting reports obscure PARG biology and its impact on cancer cell resistance to PARP1 inhibitors. Here, we found that PARG expression is upregulated in many cancers. We...
Article
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DNA double-strand break (DSB) repair is initiated by MRE11 nuclease for both homology-directed repair (HDR) and alternative end joining (Alt-EJ). Here, we found that GRB2, crucial to timely proliferative RAS/MAPK pathway activation, unexpectedly forms a biophysically validated GRB2-MRE11 (GM) complex for efficient HDR initiation. GRB2-SH2 domain ta...
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All tumors have DNA mutations, and a predictive understanding of those mutations could inform clinical treatments. However, 40% of the mutations are variants of unknown significance (VUS), with the challenge being to objectively predict whether a VUS is pathogenic and supports the tumor or whether it is benign. To objectively decode VUS, we mapped...
Article
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Alkyltransferase-like proteins (ATLs) share functional motifs with the cancer chemotherapy target O 6-alkylguanine-DNA alkyltransferase (AGT) and paradoxically protect cells from the biological effects of DNA alkylation damage, despite lacking the reactive cysteine and alkyltransferase activity of AGT. Here we determine Schizosaccharomyces pombe AT...
Article
The xeroderma pigmentosum protein A (XPA) and replication protein A (RPA) proteins fulfill essential roles in the assembly of the preincision complex in the nucleotide excision repair (NER) pathway. We have previously characterized the two interaction sites, one between the XPA N-terminal (XPA-N) disordered domain and the RPA32 C-terminal domain (R...
Preprint
Type IV collagen, the most abundant component of basement membranes, is essential for the formation of the extracellular scaffold that supports tissue architecture and function. Collagen IV is present in all multicellular species, with lower organisms typically possessing two type IV collagen genes, encoding α1 and α2 chains. The human genome encod...
Preprint
Background and Motivation: Whilst DNA repeat expansions cause numerous heritable human disorders, their origins and underlying pathological mechanisms are often unclear. Method: We collated a dataset comprising 224 human repeat expansions encompassing 203 different genes, and performed a systematic analysis with respect to key features at the DNA-,...
Preprint
Pancreatic ductal adenocarcinoma (PDAC) develops through step-wise genetic and molecular alterations including Kras mutation and inactivation of apoptotic pathways. Here, we find that development of anoikis resistance and metastasis of KrasG12D-driven PDAC in mice is accelerated by deleting Plk3, explaining the often reduced Plk3 expression in huma...
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Despite the popular use of dietary supplements during conventional cancer treatments, their impacts on the efficacies of prevalent immunotherapies, including immune checkpoint therapy (ICT), are unknown. Surprisingly, our analyses of electronic health records revealed that ICT-treated cancer patients who took vitamin E (VitE) had significantly impr...
Article
Despite the popular use of dietary supplements during conventional cancer treatments, their impacts on the efficacies of prevalent immunotherapies, including immune-checkpoint therapy (ICT), are unknown. Surprisingly, our analyses of electronic health records revealed that ICT-treated patients with cancer who took vitamin E (VitE) had significantly...
Book
Robust Computational Approaches to Defining Insights on the Interface of DNA Repair with Replication and Transcription in Cancer
Preprint
Full-text available
The XPA and RPA proteins fulfill essential roles in the assembly of the preincision complex in the nucleotide excision repair pathway. We have previously characterized the two interaction surfaces between XPA and RPA, with the RPA32 and RPA70AB subunits. Here we show that the mutations in the two individual interaction surfaces reduce NER activity...
Chapter
The biologically critical, exquisite specificity and efficiency of nucleases, such as those acting in DNA repair and replication, often emerge in the context of multiple other macromolecules. The evolved complexity also makes biologically relevant nuclease assays challenging and low-throughput. Meiotic recombination 11 homolog 1 (MRE11) is an exemp...
Chapter
Structures provide a critical breakthrough step for biological analyses, and small angle X-ray scattering (SAXS) is a powerful structural technique to study dynamic DNA repair proteins. As toxic and mutagenic repair intermediates need to be prevented from inadvertently harming the cell, DNA repair proteins often chaperone these intermediates throug...
Chapter
The massive amount of experimental DNA and RNA sequence information provides an encyclopedia for cell biology that requires computational tools for efficient interpretation. The ability to write and apply simple computing scripts propels the investigator beyond the boundaries of online analysis tools to more broadly interrogate laboratory experimen...
Article
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Topoisomerase 1 (Top1) removes transcription-associated helical stress to suppress G4-formation and its induced recombination at genomic loci containing guanine-run containing sequences. Interestingly, Top1 binds tightly to G4 structures, and its inhibition or depletion can cause elevated instability at these genomic loci. Top1 is targeted by the w...
Preprint
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Efficient DNA double strand break (DSB) repair by homologous recombination (HR), as orchestrated by histone and non-histone proteins, is critical to genome stability, replication, transcription, and cancer avoidance. Here we report that Heterochromatin Protein1 beta (HP1β) acts as a key component of the HR DNA resection step by regulating BRCA1 enr...
Article
O 6-Alkylguanine adducts in DNA are both mutagenic and toxic. Typically such adducts are repaired by O 6-alkylguanine-DNA-alkyltransferase (AGT) proteins which transfer the alkyl group to an active site Cys. Alkyltransferase-like (ATL) proteins are highly homologous to AGTs but have another amino acid such as Trp or Ala replacing the nucleophilic C...
Article
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Microdeletions and gross deletions are important causes (~20%) of human inherited disease and their genomic locations are strongly influenced by the local DNA sequence environment. This notwithstanding, no study has systematically examined their underlying generative mechanisms. Here, we obtained 42,098 pathogenic microdeletions and gross deletions...
Article
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The DNA damage response (DDR) is an organized network of multiple interwoven components evolved to repair damaged DNA and maintain genome fidelity. Conceptually the DDR includes damage sensors, transducer kinases, and effectors to maintain genomic stability and accurate transmission of genetic information. We have recently gained a substantially im...
Article
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Significance Common fragile sites (CFSs) are normal loci that are genetically unstable under normal and oncogenic replication stress. Pol eta has been proposed to play a key role in CFS replication. Here, we show that in the absence of Pol eta, replication at five specific CFS loci is perturbed, with fork pausing observed at several sites. Sequence...
Article
From initiation through progression, cancer cells are subjected to a magnitude of endogenous and exogenous stresses, which aid in their neoplastic transformation. Exposure to these classes of stress induces imbalance in cellular homeostasis and, in response, cancer cells employ informative adaptive mechanisms to rebalance biochemical processes that...
Article
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Central to genotoxic responses is their ability to sense highly specific signals to activate the appropriate repair response. We previously reported that the activation of the ASCC-ALKBH3 repair pathway is exquisitely specific to alkylation damage in human cells. Yet the mechanistic basis for the selectivity of this pathway was not immediately obvi...
Article
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We present a Chemistry and Structure Screen Integrated Efficiently (CASSIE) approach (named for Greek prophet Cassandra) to design inhibitors for cancer biology and pathogenesis. CASSIE provides an effective path to target master keys to control the repair-replication interface for cancer cells and SARS CoV-2 pathogenesis as exemplified here by spe...
Preprint
Microdeletions and gross deletions are important causes (~20%) of human inherited disease. Their genomic locations are strongly influenced by the local DNA sequence environment. Yet no systematic study has examined the generative mechanisms. Here, we obtained 42,098 pathogenic microdeletions and gross deletions from the Human Gene Mutation Database...
Article
Full-text available
The biological and functional significance of selected CASP14 targets are described by the authors of the structures. The authors highlight the most relevant features of the target proteins and discuss how well these features were reproduced in the respective submitted predictions. The overall ability to predict three-dimensional structures of prot...
Article
Stalled DNA replication fork restart after stress as orchestrated by ATR kinase, BLM helicase, and structure specific nucleases enables replication, cell survival, and genome stability. Here we unveil human exonuclease V (EXO5) as an ATR-regulated DNA structure specific nuclease and BLM partner for replication fork restart. We find that elevated EX...
Preprint
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Tyrosyl DNA phosphodiesterase 1 (TDP1) and DNA Ligase IIIα (LigIIIα) are key enzymes in single-strand break (SSB) repair. TDP1 removes 3’-tyrosine residues remaining after degradation of DNA topoisomerase (TOP) 1 cleavage complexes trapped either by DNA lesions or TOP1 inhibitors. It is not known how TDP1 is linked to subsequent processing and LigI...
Article
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DNA polymerase theta (POLθ or POLQ) is synthetic lethal with homologous recombination (HR) deficiency and is thus a candidate target for HR-deficient cancers. Through high-throughput small-molecule screens, we identified the antibiotic novobiocin (NVB) as a specific POLθ inhibitor that selectively kills HR-deficient tumor cells in vitro and in vivo...
Article
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Vigilin (Vgl1) is essential for heterochromatin formation, chromosome segregation, mRNA stability and is associated with autism-spectrum disorders and cancer, vigilin, for example, can suppress proto-oncogene c-fms expression in breast cancer. Conserved from yeast to humans, vigilin is an RNA-binding protein with 14 tandemly arranged nonidentical h...
Article
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Evolutionary selection ensures specificity and efficiency in dynamic metastable macromolecular machines that repair DNA damage without releasing toxic and mutagenic intermediates. Here we examine non-homologous end joining (NHEJ) as the primary conserved DNA double-strand break (DSB) repair process in human cells. NHEJ has exemplary key roles in ne...
Article
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Cancer cells are a major source of enzymes that modify collagen to create a stiff, fibrotic tumor stroma. High collagen lysyl hydroxylase 2 (LH2) expression promotes metastasis and is correlated with shorter survival in lung adenocarcinoma (LUAD) and other tumor types. LH2 hydroxylates lysine (Lys) residues on fibrillar collagen’s amino- and carbox...
Article
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Human uracil DNA-glycosylase (UDG) is the prototypic and first identified DNA glycosylase with a vital role in removing deaminated cytosine and incorporated uracil and 5-fluorouracil (5-FU) from DNA. UDG depletion sensitizes cells to high APOBEC3B deaminase and to pemetrexed (PEM) and floxuridine (5-FdU), which are toxic to tumor cells through inco...
Article
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Arrival of the novel SARS-CoV-2 has launched a worldwide effort to identify both pre-approved and novel therapeutics targeting the viral proteome, highlighting the urgent need for efficient drug discovery strategies. Even with effective vaccines, infection is possible, and at-risk populations would benefit from effective drug compounds that reduce...
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Article
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ABSTRACT Mechanistic studies in DNA repair have focused on roles of multi-protein DNA complexes, so how long non-coding RNAs (lncRNAs) regulate DNA repair is less well understood. Yet, lncRNA LINP1 is over-expressed in multiple cancers and confers resistance to ionizing radiation and chemotherapeutic drugs. Here, we unveil structural and mechanisti...
Article
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The XRCC1-DNA ligase III␣ complex (XL) is critical for DNA single-strand break repair, a key target for PARP inhibitors in cancer cells deficient in homolo-gous recombination. Here, we combined biophysical approaches to gain insights into the shape and con-formational flexibility of the XL as well as XRCC1 and DNA ligase III␣ (LigIII␣) alone. Struc...
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Human genome stability requires efficient repair of oxidized bases, which is initiated via damage recognition and excision by NEIL1 and other base excision repair (BER) pathway DNA glycosylases (DGs). However , the biological mechanisms underlying detection of damaged bases among the million-fold excess of undamaged bases remain enigmatic. Indeed,...
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Assembly of KU and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) at DNA double strand breaks (DSBs) forms DNA-PK holoenzyme as a critical initiating step for non-homologous end joining (NHEJ) repair of DSBs produced by radiation and chemotherapies. Advanced cryo-electron microscopy (cryo-EM) imaging together with breakthrough macromolec...
Article
Heparin and heparan sulfate (HS) are highly sulfated polysaccharides covalently bound to cell surface proteins, which directly interact with many extracellular proteins, including the transforming growth factor-β (TGFβ) family ligand antagonist, follistatin 288 (FS288). Follistatin neutralizes the TGFβ ligands, myostatin and activin A, by forming a...
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An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Cancer will directly affect the lives of over one-third of the population. The DNA Damage Response (DDR) is an intricate system involving damage recognition, cell cycle regulation, DNA repair, and ultimately cell fate determination, playing a central role in cancer etiology and therapy. Two primary therapeutic approaches involving DDR targeting inc...
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DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a key member of the phosphatidylinositol-3 kinase-like (PIKK) family of protein kinases with critical roles in DNA-double strand break repair, transcription, metastasis, mitosis, RNA processing, and innate and adaptive immunity. The absence of DNA-PKcs from many model organisms has led to...