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  • 1
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    ATM damage response and XLF repair factor are functionally redundant in joining DNA breaks (2010)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2010-12-17
    Description: Classical non-homologous DNA end-joining (NHEJ) is a major mammalian DNA double-strand-break (DSB) repair pathway. Deficiencies for classical NHEJ factors, such as XRCC4, abrogate lymphocyte development, owing to a strict requirement for classical NHEJ to join V(D)J recombination DSB intermediates. The XRCC4-like factor (XLF; also called NHEJ1) is mutated in certain immunodeficient human patients and has been implicated in classical NHEJ; however, XLF-deficient mice have relatively normal lymphocyte development and their lymphocytes support normal V(D)J recombination. The ataxia telangiectasia-mutated protein (ATM) detects DSBs and activates DSB responses by phosphorylating substrates including histone H2AX. However, ATM deficiency causes only modest V(D)J recombination and lymphocyte developmental defects, and H2AX deficiency does not have a measurable impact on these processes. Here we show that XLF, ATM and H2AX all have fundamental roles in processing and joining DNA ends during V(D)J recombination, but that these roles have been masked by unanticipated functional redundancies. Thus, combined deficiency of ATM and XLF nearly blocks mouse lymphocyte development due to an inability to process and join chromosomal V(D)J recombination DSB intermediates. Combined XLF and ATM deficiency also severely impairs classical NHEJ, but not alternative end-joining, during IgH class switch recombination. Redundant ATM and XLF functions in classical NHEJ are mediated by ATM kinase activity and are not required for extra-chromosomal V(D)J recombination, indicating a role for chromatin-associated ATM substrates. Correspondingly, conditional H2AX inactivation in XLF-deficient pro-B lines leads to V(D)J recombination defects associated with marked degradation of unjoined V(D)J ends, revealing that H2AX has a role in this process.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058373/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058373/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zha, Shan -- Guo, Chunguang -- Boboila, Cristian -- Oksenych, Valentyn -- Cheng, Hwei-Ling -- Zhang, Yu -- Wesemann, Duane R -- Yuen, Grace -- Patel, Harin -- Goff, Peter H -- Dubois, Richard L -- Alt, Frederick W -- AI007376/AI/NIAID NIH HHS/ -- AI020047/AI/NIAID NIH HHS/ -- AI076210/AI/NIAID NIH HHS/ -- K08 AI089972/AI/NIAID NIH HHS/ -- K08 AI089972-01/AI/NIAID NIH HHS/ -- P01 AI076210/AI/NIAID NIH HHS/ -- P01 AI076210-03/AI/NIAID NIH HHS/ -- R01 AI020047/AI/NIAID NIH HHS/ -- R01 AI020047-28/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Jan 13;469(7329):250-4. doi: 10.1038/nature09604. Epub 2010 Dec 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, The Children's Hospital, the Immune Disease Institute and the Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21160472" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/genetics/*metabolism ; Cell Line, Transformed ; Chromatin/metabolism ; Chromosomes, Mammalian/genetics/metabolism ; *DNA Breaks, Double-Stranded ; *DNA Repair ; DNA-Binding Proteins/deficiency/genetics/*metabolism ; Embryo, Mammalian/embryology/metabolism ; *Gene Rearrangement, B-Lymphocyte/genetics ; Histones/*metabolism ; Mice ; Precursor Cells, B-Lymphoid/cytology/metabolism ; Protein-Serine-Threonine Kinases/deficiency/genetics/*metabolism ; *Recombination, Genetic ; Tumor Suppressor Proteins/deficiency/genetics/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    CTCF-binding elements mediate control of V(D)J recombination (2011)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2011-09-13
    Description: Immunoglobulin heavy chain (IgH) variable region exons are assembled from V(H), D and J(H) gene segments in developing B lymphocytes. Within the 2.7-megabase mouse Igh locus, V(D)J recombination is regulated to ensure specific and diverse antibody repertoires. Here we report in mice a key Igh V(D)J recombination regulatory region, termed intergenic control region 1 (IGCR1), which lies between the V(H) and D clusters. Functionally, IGCR1 uses CTCF looping/insulator factor-binding elements and, correspondingly, mediates Igh loops containing distant enhancers. IGCR1 promotes normal B-cell development and balances antibody repertoires by inhibiting transcription and rearrangement of D(H)-proximal V(H) gene segments and promoting rearrangement of distal V(H) segments. IGCR1 maintains ordered and lineage-specific V(H)(D)J(H) recombination by suppressing V(H) joining to D segments not joined to J(H) segments, and V(H) to DJ(H) joins in thymocytes, respectively. IGCR1 is also required for feedback regulation and allelic exclusion of proximal V(H)-to-DJ(H) recombination. Our studies elucidate a long-sought Igh V(D)J recombination control region and indicate a new role for the generally expressed CTCF protein.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3342812/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3342812/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Guo, Chunguang -- Yoon, Hye Suk -- Franklin, Andrew -- Jain, Suvi -- Ebert, Anja -- Cheng, Hwei-Ling -- Hansen, Erica -- Despo, Orion -- Bossen, Claudia -- Vettermann, Christian -- Bates, Jamie G -- Richards, Nicholas -- Myers, Darienne -- Patel, Harin -- Gallagher, Michael -- Schlissel, Mark S -- Murre, Cornelis -- Busslinger, Meinrad -- Giallourakis, Cosmas C -- Alt, Frederick W -- AI40227/AI/NIAID NIH HHS/ -- CA054198-20/CA/NCI NIH HHS/ -- K08 AI070839/AI/NIAID NIH HHS/ -- P30 DK043351/DK/NIDDK NIH HHS/ -- R01 AI020047/AI/NIAID NIH HHS/ -- R01 AI020047-27/AI/NIAID NIH HHS/ -- R01 AI020047-28/AI/NIAID NIH HHS/ -- R01 AI020047-29/AI/NIAID NIH HHS/ -- R01 AI20047/AI/NIAID NIH HHS/ -- R01 HL48702/HL/NHLBI NIH HHS/ -- R37 AI040227/AI/NIAID NIH HHS/ -- T32 CA009151/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Sep 11;477(7365):424-30. doi: 10.1038/nature10495.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, The Children's Hospital, The Immune Disease Institute, Department of Genetics, Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21909113" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; B-Lymphocytes/cytology/metabolism ; Cell Lineage/genetics ; Chromosomes, Mammalian/genetics/metabolism ; DNA, Intergenic/*genetics ; Enhancer Elements, Genetic/genetics ; Feedback, Physiological ; Gene Rearrangement, B-Lymphocyte, Heavy Chain/*genetics ; Germ Cells/metabolism ; Immunoglobulin Heavy Chains/genetics ; Immunoglobulin Variable Region/genetics ; Mice ; Mutation/genetics ; Recombination, Genetic/*genetics ; Regulatory Sequences, Nucleic Acid/*genetics ; Repressor Proteins/*metabolism ; Thymus Gland/cytology ; Transcription, Genetic/genetics ; VDJ Exons/*genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
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    The NAD-dependent deacetylase SIRT2 is required for programmed necrosis (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-12-04
    Description: Although initially viewed as unregulated, increasing evidence suggests that cellular necrosis often proceeds through a specific molecular program. In particular, death ligands such as tumour necrosis factor (TNF)-alpha activate necrosis by stimulating the formation of a complex containing receptor-interacting protein 1 (RIP1) and receptor-interacting protein 3 (RIP3). Relatively little is known regarding how this complex formation is regulated. Here, we show that the NAD-dependent deacetylase SIRT2 binds constitutively to RIP3 and that deletion or knockdown of SIRT2 prevents formation of the RIP1-RIP3 complex in mice. Furthermore, genetic or pharmacological inhibition of SIRT2 blocks cellular necrosis induced by TNF-alpha. We further demonstrate that RIP1 is a critical target of SIRT2-dependent deacetylation. Using gain- and loss-of-function mutants, we demonstrate that acetylation of RIP1 lysine 530 modulates RIP1-RIP3 complex formation and TNF-alpha-stimulated necrosis. In the setting of ischaemia-reperfusion injury, RIP1 is deacetylated in a SIRT2-dependent fashion. Furthermore, the hearts of Sirt2(-/-) mice, or wild-type mice treated with a specific pharmacological inhibitor of SIRT2, show marked protection from ischaemic injury. Taken together, these results implicate SIRT2 as an important regulator of programmed necrosis and indicate that inhibitors of this deacetylase may constitute a novel approach to protect against necrotic injuries, including ischaemic stroke and myocardial infarction.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Narayan, Nisha -- Lee, In Hye -- Borenstein, Ronen -- Sun, Junhui -- Wong, Renee -- Tong, Guang -- Fergusson, Maria M -- Liu, Jie -- Rovira, Ilsa I -- Cheng, Hwei-Ling -- Wang, Guanghui -- Gucek, Marjan -- Lombard, David -- Alt, Fredrick W -- Sack, Michael N -- Murphy, Elizabeth -- Cao, Liu -- Finkel, Toren -- Intramural NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Dec 13;492(7428):199-204. doi: 10.1038/nature11700. Epub 2012 Nov 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Molecular Medicine, National Heart, Lung and Blood Institute, NIH, Bethesda, Maryland 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23201684" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylation ; Animals ; Cell Line ; Female ; HEK293 Cells ; HeLa Cells ; Humans ; Jurkat Cells ; Male ; Mice ; Necrosis/*enzymology ; Nuclear Pore Complex Proteins/metabolism ; Protein Binding ; Receptor-Interacting Protein Serine-Threonine Kinases/metabolism ; Sirtuin 2/*genetics/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 4
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    Chromatin regulation by Brg1 underlies heart muscle development and disease (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-07-03
    Description: Cardiac hypertrophy and failure are characterized by transcriptional reprogramming of gene expression. Adult cardiomyocytes in mice primarily express alpha-myosin heavy chain (alpha-MHC, also known as Myh6), whereas embryonic cardiomyocytes express beta-MHC (also known as Myh7). Cardiac stress triggers adult hearts to undergo hypertrophy and a shift from alpha-MHC to fetal beta-MHC expression. Here we show that Brg1, a chromatin-remodelling protein, has a critical role in regulating cardiac growth, differentiation and gene expression. In embryos, Brg1 promotes myocyte proliferation by maintaining Bmp10 and suppressing p57(kip2) expression. It preserves fetal cardiac differentiation by interacting with histone deacetylase (HDAC) and poly (ADP ribose) polymerase (PARP) to repress alpha-MHC and activate beta-MHC. In adults, Brg1 (also known as Smarca4) is turned off in cardiomyocytes. It is reactivated by cardiac stresses and forms a complex with its embryonic partners, HDAC and PARP, to induce a pathological alpha-MHC to beta-MHC shift. Preventing Brg1 re-expression decreases hypertrophy and reverses this MHC switch. BRG1 is activated in certain patients with hypertrophic cardiomyopathy, its level correlating with disease severity and MHC changes. Our studies show that Brg1 maintains cardiomyocytes in an embryonic state, and demonstrate an epigenetic mechanism by which three classes of chromatin-modifying factors-Brg1, HDAC and PARP-cooperate to control developmental and pathological gene expression.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2898892/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2898892/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hang, Calvin T -- Yang, Jin -- Han, Pei -- Cheng, Hsiu-Ling -- Shang, Ching -- Ashley, Euan -- Zhou, Bin -- Chang, Ching-Pin -- R01 HL085345/HL/NHLBI NIH HHS/ -- R01 HL085345-03S1/HL/NHLBI NIH HHS/ -- R01 HL085345-04/HL/NHLBI NIH HHS/ -- T32 CA009302/CA/NCI NIH HHS/ -- England -- Nature. 2010 Jul 1;466(7302):62-7. doi: 10.1038/nature09130.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20596014" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cardiomegaly/*genetics/*metabolism/pathology ; Cell Differentiation ; Cell Proliferation ; Chromatin/*genetics ; DNA Helicases/deficiency/genetics/*metabolism ; Embryo Loss/genetics ; Embryo, Mammalian/metabolism ; Gene Expression Regulation, Developmental ; Histone Deacetylases/metabolism ; Humans ; Mice ; Myocardium/cytology/*metabolism/pathology ; Myosin Heavy Chains/genetics/metabolism ; Nuclear Proteins/deficiency/genetics/*metabolism ; Poly(ADP-ribose) Polymerases/metabolism ; Transcription Factors/deficiency/genetics/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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