keyword
MENU ▼
Read by QxMD icon Read
search

Frederick W Alt

keyword
https://www.readbyqxmd.com/read/29311308/dna-double-strand-break-response-factors-influence-end-joining-features-of-igh-class-switch-and-general-translocation-junctions
#1
Rohit A Panchakshari, Xuefei Zhang, Vipul Kumar, Zhou Du, Pei-Chi Wei, Jennifer Kao, Junchao Dong, Frederick W Alt
Ig heavy chain (IgH) class switch recombination (CSR) in B lymphocytes switches IgH constant regions to change antibody functions. CSR is initiated by DNA double-strand breaks (DSBs) within a donor IgH switch (S) region and a downstream acceptor S region. CSR is completed by fusing donor and acceptor S region DSB ends by classical nonhomologous end-joining (C-NHEJ) and, in its absence, by alternative end-joining that is more biased to use longer junctional microhomologies (MHs). Deficiency for DSB response (DSBR) factors, including ataxia telangiectasia-mutated (ATM) and 53BP1, variably impair CSR end-joining, with 53BP1 deficiency having the greatest impact...
January 8, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29168504/mechanism-of-tandem-duplication-formation-in-brca1-mutant-cells
#2
Nicholas A Willis, Richard L Frock, Francesca Menghi, Erin E Duffey, Arvind Panday, Virginia Camacho, E Paul Hasty, Edison T Liu, Frederick W Alt, Ralph Scully
Small, approximately 10-kilobase microhomology-mediated tandem duplications are abundant in the genomes of BRCA1-linked but not BRCA2-linked breast cancer. Here we define the mechanism underlying this rearrangement signature. We show that, in primary mammalian cells, BRCA1, but not BRCA2, suppresses the formation of tandem duplications at a site-specific chromosomal replication fork barrier imposed by the binding of Tus proteins to an array of Ter sites. BRCA1 has no equivalent role at chromosomal double-stranded DNA breaks, indicating that tandem duplications form specifically at stalled forks...
November 22, 2017: Nature
https://www.readbyqxmd.com/read/29158395/histone-methyltransferase-mmset-promotes-aid-mediated-dna-breaks-at-the-donor-switch-region-during-class-switch-recombination
#3
Hai Vu Nguyen, Junchao Dong, Rohit A Panchakshari, Vipul Kumar, Frederick W Alt, Jean-Christophe Bories
In B cells, Ig class switch recombination (CSR) is initiated by activation-induced cytidine deaminase (AID), the activity of which leads to DNA double-strand breaks (DSBs) within IgH switch (S) regions. Preferential targeting of AID-mediated DSBs to S sequences is critical for allowing diversification of antibody functions, while minimizing potential off-target oncogenic events. Here, we used gene targeted inactivation of histone methyltransferase (HMT) multiple myeloma SET domain (MMSET) in mouse B cells and the CH12F3 cell line to explore its role in CSR...
November 20, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28759779/synthetic-lethality-between-murine-dna-repair-factors-xlf-and-dna-pkcs-is-rescued-by-inactivation-of-ku70
#4
Mengtan Xing, Magnar Bjørås, Jeremy A Daniel, Frederick W Alt, Valentyn Oksenych
DNA double-strand breaks (DSBs) are recognized and repaired by the Classical Non-Homologous End-Joining (C-NHEJ) and Homologous Recombination pathways. C-NHEJ includes the core Ku70 and Ku80 (or Ku86) heterodimer that binds DSBs and thus promotes recruitment of accessory downstream NHEJ factors XLF, PAXX, DNA-PKcs, Artemis and other core subunits, XRCC4 and DNA Ligase 4 (Lig4). In the absence of core C-NHEJ factors, DNA repair can be performed by Alternative End-Joining, which likely depends on DNA Ligase 1 and DNA Ligase 3...
September 2017: DNA Repair
https://www.readbyqxmd.com/read/28757211/aid-recognizes-structured-dna-for-class-switch-recombination
#5
Qi Qiao, Li Wang, Fei-Long Meng, Joyce K Hwang, Frederick W Alt, Hao Wu
Activation-induced cytidine deaminase (AID) initiates both class switch recombination (CSR) and somatic hypermutation (SHM) in antibody diversification. Mechanisms of AID targeting and catalysis remain elusive despite its critical immunological roles and off-target effects in tumorigenesis. Here, we produced active human AID and revealed its preferred recognition and deamination of structured substrates. G-quadruplex (G4)-containing substrates mimicking the mammalian immunoglobulin switch regions are particularly good AID substrates in vitro...
August 3, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28747530/sequence-intrinsic-somatic-mutation-mechanisms-contribute-to-affinity-maturation-of-vrc01-class-hiv-1-broadly-neutralizing-antibodies
#6
Joyce K Hwang, Chong Wang, Zhou Du, Robin M Meyers, Thomas B Kepler, Donna Neuberg, Peter D Kwong, John R Mascola, M Gordon Joyce, Mattia Bonsignori, Barton F Haynes, Leng-Siew Yeap, Frederick W Alt
Variable regions of Ig chains provide the antigen recognition portion of B-cell receptors and derivative antibodies. Ig heavy-chain variable region exons are assembled developmentally from V, D, J gene segments. Each variable region contains three antigen-contacting complementarity-determining regions (CDRs), with CDR1 and CDR2 encoded by the V segment and CDR3 encoded by the V(D)J junction region. Antigen-stimulated germinal center (GC) B cells undergo somatic hypermutation (SHM) of V(D)J exons followed by selection for SHMs that increase antigen-binding affinity...
August 8, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28199309/phosphatidylinositol-3-kinase-%C3%AE-blockade-increases-genomic-instability-in-b-cells
#7
Mara Compagno, Qi Wang, Chiara Pighi, Taek-Chin Cheong, Fei-Long Meng, Teresa Poggio, Leng-Siew Yeap, Elif Karaca, Rafael B Blasco, Fernanda Langellotto, Chiara Ambrogio, Claudia Voena, Adrian Wiestner, Siddha N Kasar, Jennifer R Brown, Jing Sun, Catherine J Wu, Monica Gostissa, Frederick W Alt, Roberto Chiarle
Activation-induced cytidine deaminase (AID) is a B-cell-specific enzyme that targets immunoglobulin genes to initiate class switch recombination and somatic hypermutation. In addition, through off-target activity, AID has a much broader effect on genomic instability by initiating oncogenic chromosomal translocations and mutations involved in the development and progression of lymphoma. AID expression is tightly regulated in B cells and its overexpression leads to enhanced genomic instability and lymphoma formation...
February 23, 2017: Nature
https://www.readbyqxmd.com/read/28133799/human-ig-knockin-mice-to-study-the-development-and-regulation-of-hiv-1-broadly-neutralizing-antibodies
#8
REVIEW
Laurent Verkoczy, Frederick W Alt, Ming Tian
A major challenge for HIV-1 vaccine research is developing a successful immunization approach for inducing broadly neutralizing antibodies (bnAbs). A key shortcoming in meeting this challenge has been the lack of animal models capable of identifying impediments limiting bnAb induction and ranking vaccine strategies for their ability to promote bnAb development. Since 2010, immunoglobulin knockin (KI) technology, involving inserting functional rearranged human variable exons into the mouse IgH and IgL loci has been used to express bnAbs in mice...
January 2017: Immunological Reviews
https://www.readbyqxmd.com/read/27613698/an-ectopic-ctcf-binding-element-inhibits-tcrd-rearrangement-by-limiting-contact-between-v%C3%AE-and-d%C3%AE-gene-segments
#9
Liang Chen, Lijuan Zhao, Frederick W Alt, Michael S Krangel
Chromatin looping mediated by the CCCTC binding factor (CTCF) regulates V(D)J recombination at Ag receptor loci. CTCF-mediated looping can influence recombination signal sequence (RSS) accessibility by regulating enhancer activation of germline promoters. CTCF-mediated looping has also been shown to limit directional tracking of the RAG recombinase along chromatin, and to regulate long-distance interactions between RSSs, independent of the RAG recombinase. However, in all prior instances in which CTCF-mediated looping was shown to influence V(D)J recombination, it was not possible to fully resolve the relative contributions to the V(D)J recombination phenotype of changes in accessibility, RAG tracking, and RAG-independent long-distance interactions...
October 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27610571/induction-of-hiv-neutralizing-antibody-lineages-in-mice-with-diverse-precursor-repertoires
#10
Ming Tian, Cheng Cheng, Xuejun Chen, Hongying Duan, Hwei-Ling Cheng, Mai Dao, Zizhang Sheng, Michael Kimble, Lingshu Wang, Sherry Lin, Stephen D Schmidt, Zhou Du, M Gordon Joyce, Yiwei Chen, Brandon J DeKosky, Yimin Chen, Erica Normandin, Elizabeth Cantor, Rita E Chen, Nicole A Doria-Rose, Yi Zhang, Wei Shi, Wing-Pui Kong, Misook Choe, Amy R Henry, Farida Laboune, Ivelin S Georgiev, Pei-Yi Huang, Suvi Jain, Andrew T McGuire, Eric Georgeson, Sergey Menis, Daniel C Douek, William R Schief, Leonidas Stamatatos, Peter D Kwong, Lawrence Shapiro, Barton F Haynes, John R Mascola, Frederick W Alt
The design of immunogens that elicit broadly reactive neutralizing antibodies (bnAbs) has been a major obstacle to HIV-1 vaccine development. One approach to assess potential immunogens is to use mice expressing precursors of human bnAbs as vaccination models. The bnAbs of the VRC01-class derive from the IGHV1-2 immunoglobulin heavy chain and neutralize a wide spectrum of HIV-1 strains via targeting the CD4 binding site of the envelope glycoprotein gp120. We now describe a mouse vaccination model that allows a germline human IGHV1-2(∗)02 segment to undergo normal V(D)J recombination and, thereby, leads to the generation of peripheral B cells that express a highly diverse repertoire of VRC01-related receptors...
September 8, 2016: Cell
https://www.readbyqxmd.com/read/27601633/paxx-and-xlf-dna-repair-factors-are-functionally-redundant-in-joining-dna-breaks-in-a-g1-arrested-progenitor-b-cell-line
#11
Vipul Kumar, Frederick W Alt, Richard L Frock
Classical nonhomologous end joining (C-NHEJ) is a major mammalian DNA double-strand break (DSB) repair pathway. Core C-NHEJ factors, such as XRCC4, are required for joining DSB intermediates of the G1 phase-specific V(D)J recombination reaction in progenitor lymphocytes. Core factors also contribute to joining DSBs in cycling mature B-lineage cells, including DSBs generated during antibody class switch recombination (CSR) and DSBs generated by ionizing radiation. The XRCC4-like-factor (XLF) C-NHEJ protein is dispensable for V(D)J recombination in normal cells, but because of functional redundancy, it is absolutely required for this process in cells deficient for the ataxia telangiectasia-mutated (ATM) DSB response factor...
September 20, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27526713/orientation-specific-rag-activity-in-chromosomal-loop-domains-contributes-to-tcrd-v-d-j-recombination-during-t-cell-development
#12
Lijuan Zhao, Richard L Frock, Zhou Du, Jiazhi Hu, Liang Chen, Michael S Krangel, Frederick W Alt
T cell antigen receptor δ (Tcrd) variable region exons are assembled by RAG-initiated V(D)J recombination events in developing γδ thymocytes. Here, we use linear amplification-mediated high-throughput genome-wide translocation sequencing (LAM-HTGTS) to map hundreds of thousands of RAG-initiated Tcrd D segment (Trdd1 and Trdd2) rearrangements in CD4(-)CD8(-) double-negative thymocyte progenitors differentiated in vitro from bone marrow-derived hematopoietic stem cells. We find that Trdd2 joins directly to Trdv, Trdd1, and Trdj segments, whereas Trdd1 joining is ordered with joining to Trdd2, a prerequisite for further rearrangement...
August 22, 2016: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/27354528/highly-sensitive-and-unbiased-approach-for-elucidating-antibody-repertoires
#13
Sherry G Lin, Zhaoqing Ba, Zhou Du, Yu Zhang, Jiazhi Hu, Frederick W Alt
Developing B lymphocytes undergo V(D)J recombination to assemble germ-line V, D, and J gene segments into exons that encode the antigen-binding variable region of Ig heavy (H) and light (L) chains. IgH and IgL chains associate to form the B-cell receptor (BCR), which, upon antigen binding, activates B cells to secrete BCR as an antibody. Each of the huge number of clonally independent B cells expresses a unique set of IgH and IgL variable regions. The ability of V(D)J recombination to generate vast primary B-cell repertoires results from a combinatorial assortment of large numbers of different V, D, and J segments, coupled with diversification of the junctions between them to generate the complementary determining region 3 (CDR3) for antigen contact...
July 12, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27183648/pillars-article-a-functional-t3-molecule-associated-with-a-novel-heterodimer-on-the-surface-of-immature-human-thymocytes-nature-1986-322-179-181
#14
Ilan Bank, Ronald A DePinho, Michael B Brenner, Judy Cassimeris, Frederick W Alt, Leonard Chess
No abstract text is available yet for this article.
May 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27031497/detecting-dna-double-stranded-breaks-in-mammalian-genomes-by-linear-amplification-mediated-high-throughput-genome-wide-translocation-sequencing
#15
Jiazhi Hu, Robin M Meyers, Junchao Dong, Rohit A Panchakshari, Frederick W Alt, Richard L Frock
Unbiased, high-throughput assays for detecting and quantifying DNA double-stranded breaks (DSBs) across the genome in mammalian cells will facilitate basic studies of the mechanisms that generate and repair endogenous DSBs. They will also enable more applied studies, such as those to evaluate the on- and off-target activities of engineered nucleases. Here we describe a linear amplification-mediated high-throughput genome-wide sequencing (LAM-HTGTS) method for the detection of genome-wide 'prey' DSBs via their translocation in cultured mammalian cells to a fixed 'bait' DSB...
May 2016: Nature Protocols
https://www.readbyqxmd.com/read/26873106/transcription-associated-processes-cause-dna-double-strand-breaks-and-translocations-in-neural-stem-progenitor-cells
#16
Bjoern Schwer, Pei-Chi Wei, Amelia N Chang, Jennifer Kao, Zhou Du, Robin M Meyers, Frederick W Alt
High-throughput, genome-wide translocation sequencing (HTGTS) studies of activated B cells have revealed that DNA double-strand breaks (DSBs) capable of translocating to defined bait DSBs are enriched around the transcription start sites (TSSs) of active genes. We used the HTGTS approach to investigate whether a similar phenomenon occurs in primary neural stem/progenitor cells (NSPCs). We report that breakpoint junctions indeed are enriched around TSSs that were determined to be active by global run-on sequencing analyses of NSPCs...
February 23, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/26871630/long-neural-genes-harbor-recurrent-dna-break-clusters-in-neural-stem-progenitor-cells
#17
Pei-Chi Wei, Amelia N Chang, Jennifer Kao, Zhou Du, Robin M Meyers, Frederick W Alt, Bjoern Schwer
Repair of DNA double-strand breaks (DSBs) by non-homologous end joining is critical for neural development, and brain cells frequently contain somatic genomic variations that might involve DSB intermediates. We now use an unbiased, high-throughput approach to identify genomic regions harboring recurrent DSBs in primary neural stem/progenitor cells (NSPCs). We identify 27 recurrent DSB clusters (RDCs), and remarkably, all occur within gene bodies. Most of these NSPC RDCs were detected only upon mild, aphidicolin-induced replication stress, providing a nucleotide-resolution view of replication-associated genomic fragile sites...
February 11, 2016: Cell
https://www.readbyqxmd.com/read/26843073/frederick-w-alt-received-the-2015-szent-gy%C3%A3-rgi-prize-for-progress-in-cancer-research
#18
Peter Scully, Jie Zhao, Sujuan Ba
The Szent-Györgyi Prize for Progress in Cancer Research is a prestigious scientific award established by the National Foundation for Cancer Research (NFCR)--a leading cancer research charitable organization in the United States that is committed to supporting scientific research and public education relating to the prevention, early diagnosis, better treatments, and ultimately, a cure for cancer. Each year, the Szent-Györgyi Prize honors an outstanding researcher, nominated by colleagues or peers, who has contributed outstanding, significant research to the fight against cancer, and whose accomplishments have helped improve treatment options for cancer patients...
February 3, 2016: Chinese Journal of Cancer
https://www.readbyqxmd.com/read/26831080/sequential-activation-and-distinct-functions-for-distal-and-proximal-modules-within-the-igh-3-regulatory-region
#19
Armand Garot, Marie Marquet, Alexis Saintamand, Sébastien Bender, Sandrine Le Noir, Pauline Rouaud, Claire Carrion, Zéliha Oruc, Anne-Gaëlle Bébin, Jeanne Moreau, Kevin Lebrigand, Yves Denizot, Frederick W Alt, Michel Cogné, Eric Pinaud
As a master regulator of functional Ig heavy chain (IgH) expression, the IgH 3' regulatory region (3'RR) controls multiple transcription events at various stages of B-cell ontogeny, from newly formed B cells until the ultimate plasma cell stage. The IgH 3'RR plays a pivotal role in early B-cell receptor expression, germ-line transcription preceding class switch recombination, interactions between targeted switch (S) regions, variable region transcription before somatic hypermutation, and antibody heavy chain production, but the functional ranking of its different elements is still inaccurate, especially that of its evolutionarily conserved quasi-palindromic structure...
February 9, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/26593423/chromosomal-loop-domains-direct-the-recombination-of-antigen-receptor-genes
#20
Jiazhi Hu, Yu Zhang, Lijuan Zhao, Richard L Frock, Zhou Du, Robin M Meyers, Fei-long Meng, David G Schatz, Frederick W Alt
RAG initiates antibody V(D)J recombination in developing lymphocytes by generating "on-target" DNA breaks at matched pairs of bona fide recombination signal sequences (RSSs). We employ bait RAG-generated breaks in endogenous or ectopically inserted RSS pairs to identify huge numbers of RAG "off-target" breaks. Such breaks occur at the simple CAC motif that defines the RSS cleavage site and are largely confined within convergent CTCF-binding element (CBE)-flanked loop domains containing bait RSS pairs. Marked orientation dependence of RAG off-target activity within loops spanning up to 2 megabases implies involvement of linear tracking...
November 5, 2015: Cell
keyword
keyword
21996
1
2
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read
×

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"