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Article: Single Molecule Analysis of Laser Localized Interstrand Crosslinks.

Huang, Jing / Gali, Himabindu / Paramasivam, Manikandan / Muniandy, Parameswary / Gichimu, Julia / Bellani, Marina A / Seidman, Michael M

Frontiers in genetics

2016 Volume 7, Page(s) 84

Abstract: DNA interstrand crosslinks (ICLs) block unwinding of the double helix, and have always been regarded as major challenges to replication and transcription. Compounds that form these lesions are very toxic and are frequently used in cancer chemotherapy. We ...

Abstract	DNA interstrand crosslinks (ICLs) block unwinding of the double helix, and have always been regarded as major challenges to replication and transcription. Compounds that form these lesions are very toxic and are frequently used in cancer chemotherapy. We have developed two strategies, both based on immunofluorescence (IF), for studying cellular responses to ICLs. The basis of each is psoralen, a photoactive (by long wave ultraviolet light, UVA) DNA crosslinking agent, to which we have linked an antigen tag. In the one approach, we have taken advantage of DNA fiber and immuno-quantum dot technologies for visualizing the encounter of replication forks with ICLs induced by exposure to UVA lamps. In the other, psoralen ICLs are introduced into nuclei in live cells in regions of interest defined by a UVA laser. The antigen tag can be displayed by conventional IF, as can the recruitment and accumulation of DNA damage response proteins to the laser localized ICLs. However, substantial difference between the technologies creates considerable uncertainty as to whether conclusions from one approach are applicable to those of the other. In this report, we have employed the fiber/quantum dot methodology to determine lesion density and spacing on individual DNA molecules carrying laser localized ICLs. We have performed the same measurements on DNA fibers with ICLs induced by exposure of psoralen to UVA lamps. Remarkably, we find little difference in the adduct distribution on fibers prepared from cells exposed to the different treatment protocols. Furthermore, there is considerable similarity in patterns of replication in the vicinity of the ICLs introduced by the two techniques.
Language	English
Publishing date	2016-05-09
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606823-0
ISSN	1664-8021
ISSN	1664-8021
DOI	10.3389/fgene.2016.00084
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Article ; Online: Fanconi anemia group J helicase and MRE11 nuclease interact to facilitate the DNA damage response.

Suhasini, Avvaru N / Sommers, Joshua A / Muniandy, Parameswary A / Coulombe, Yan / Cantor, Sharon B / Masson, Jean-Yves / Seidman, Michael M / Brosh, Robert M

Molecular and cellular biology

2013 Volume 33, Issue 11, Page(s) 2212–2227

Abstract: FANCJ mutations are linked to Fanconi anemia (FA) and increase breast cancer risk. FANCJ encodes a DNA helicase implicated in homologous recombination (HR) repair of double-strand breaks (DSBs) and interstrand cross-links (ICLs), but its mechanism of ... ...

Abstract	FANCJ mutations are linked to Fanconi anemia (FA) and increase breast cancer risk. FANCJ encodes a DNA helicase implicated in homologous recombination (HR) repair of double-strand breaks (DSBs) and interstrand cross-links (ICLs), but its mechanism of action is not well understood. Here we show with live-cell imaging that FANCJ recruitment to laser-induced DSBs but not psoralen-induced ICLs is dependent on nuclease-active MRE11. FANCJ interacts directly with MRE11 and inhibits its exonuclease activity in a specific manner, suggesting that FANCJ regulates the MRE11 nuclease to facilitate DSB processing and appropriate end resection. Cells deficient in FANCJ and MRE11 show increased ionizing radiation (IR) resistance, reduced numbers of γH2AX and RAD51 foci, and elevated numbers of DNA-dependent protein kinase catalytic subunit foci, suggesting that HR is compromised and the nonhomologous end-joining (NHEJ) pathway is elicited to help cells cope with IR-induced strand breaks. Interplay between FANCJ and MRE11 ensures a normal response to IR-induced DSBs, whereas FANCJ involvement in ICL repair is regulated by MLH1 and the FA pathway. Our findings are discussed in light of the current model for HR repair.
MeSH term(s)	Acid Anhydride Hydrolases ; Basic-Leucine Zipper Transcription Factors/genetics ; Basic-Leucine Zipper Transcription Factors/metabolism ; Carrier Proteins/genetics ; Carrier Proteins/metabolism ; Chromosomal Instability ; DNA Breaks, Double-Stranded ; DNA Damage ; DNA Repair/physiology ; DNA Repair/radiation effects ; DNA Repair Enzymes/genetics ; DNA Repair Enzymes/metabolism ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Endodeoxyribonucleases ; Fanconi Anemia Complementation Group Proteins/genetics ; Fanconi Anemia Complementation Group Proteins/metabolism ; Ficusin/pharmacology ; HeLa Cells/drug effects ; HeLa Cells/radiation effects ; Humans ; MRE11 Homologue Protein ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Radiation, Ionizing ; Recombinational DNA Repair
Chemical Substances	BACH1 protein, human ; Basic-Leucine Zipper Transcription Factors ; Carrier Proteins ; DNA-Binding Proteins ; Fanconi Anemia Complementation Group Proteins ; MRE11 protein, human ; Nuclear Proteins ; Endodeoxyribonucleases (EC 3.1.-) ; MRE11 Homologue Protein (EC 3.1.-) ; RBBP8 protein, human (EC 3.1.-) ; Acid Anhydride Hydrolases (EC 3.6.-) ; RAD50 protein, human (EC 3.6.-) ; DNA Repair Enzymes (EC 6.5.1.-) ; Ficusin (KTZ7ZCN2EX)
Language	English
Publishing date	2013-03-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
ZDB-ID	779397-2
ISSN	1098-5549 ; 0270-7306
ISSN (online)	1098-5549
ISSN	0270-7306
DOI	10.1128/MCB.01256-12
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Article: Repair of Laser-localized DNA Interstrand Cross-links in G₁ Phase Mammalian Cells

Muniandy, Parameswary A / Thapa, Dennis / Thazhathveetil, Arun Kalliat / Liu, Su-ting / Seidman, Michael M

Journal of biological chemistry. 2009 Oct. 9, v. 284, no. 41

2009

Abstract: Interstrand cross-links (ICLs) are absolute blocks to transcription and replication and can provoke genomic instability and cell death. Studies in bacteria define a two-stage repair scheme, the first involving recognition and incision on either side of ... ...

Abstract	Interstrand cross-links (ICLs) are absolute blocks to transcription and replication and can provoke genomic instability and cell death. Studies in bacteria define a two-stage repair scheme, the first involving recognition and incision on either side of the cross-link on one strand (unhooking), followed by recombinational repair or lesion bypass synthesis. The resultant monoadduct is removed in a second stage by nucleotide excision repair. In mammalian cells, there are multiple, but poorly defined, pathways, with much current attention on repair in S phase. However, many questions remain, including the efficiency of repair in the absence of replication, the factors involved in cross-link recognition, and the timing and demarcation of the first and second repair cycles. We have followed the repair of laser-localized lesions formed by psoralen (cross-links/monoadducts) and angelicin (only monoadducts) in mammalian cells. Both were repaired in G₁ phase by nucleotide excision repair-dependent pathways. Removal of psoralen adducts was blocked in XPC-deficient cells but occurred with wild type kinetics in cells deficient in DDB2 protein (XPE). XPC protein was rapidly recruited to psoralen adducts. However, accumulation of DDB2 was slow and XPC-dependent. Inhibition of repair DNA synthesis did not interfere with DDB2 recruitment to angelicin but eliminated recruitment to psoralen. Our results demonstrate an efficient ICL repair pathway in G₁ phase cells dependent on XPC, with entry of DDB2 only after repair synthesis that completes the first repair cycle. DDB2 accumulation at sites of cross-link repair is a marker for the start of the second repair cycle.
Language	English
Dates of publication	2009-1009
Size	p. 27908-27917.
Publishing place	American Society for Biochemistry and Molecular Biology
Document type	Article
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
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Article ; Online: DNA interstrand crosslink repair in mammalian cells: step by step.

Muniandy, Parameswary A / Liu, Jia / Majumdar, Alokes / Liu, Su-ting / Seidman, Michael M

Critical reviews in biochemistry and molecular biology

2009 Volume 45, Issue 1, Page(s) 23–49

Abstract: Interstrand DNA crosslinks (ICLs) are formed by natural products of metabolism and by chemotherapeutic reagents. Work in E. coli identified a two cycle repair scheme involving incisions on one strand on either side of the ICL (unhooking) producing a ... ...

Abstract	Interstrand DNA crosslinks (ICLs) are formed by natural products of metabolism and by chemotherapeutic reagents. Work in E. coli identified a two cycle repair scheme involving incisions on one strand on either side of the ICL (unhooking) producing a gapped intermediate with the incised oligonucleotide attached to the intact strand. The gap is filled by recombinational repair or lesion bypass synthesis. The remaining monoadduct is then removed by nucleotide excision repair (NER). Despite considerable effort, our understanding of each step in mammalian cells is still quite limited. In part this reflects the variety of crosslinking compounds, each with distinct structural features, used by different investigators. Also, multiple repair pathways are involved, variably operative during the cell cycle. G(1) phase repair requires functions from NER, although the mechanism of recognition has not been determined. Repair can be initiated by encounters with the transcriptional apparatus, or a replication fork. In the case of the latter, the reconstruction of a replication fork, stalled or broken by collision with an ICL, adds to the complexity of the repair process. The enzymology of unhooking, the identity of the lesion bypass polymerases required to fill the first repair gap, and the functions involved in the second repair cycle are all subjects of active inquiry. Here we will review current understanding of each step in ICL repair in mammalian cells.
MeSH term(s)	Animals ; Cell Cycle/genetics ; Cross-Linking Reagents/pharmacology ; DNA/drug effects ; DNA/genetics ; DNA/metabolism ; DNA Damage ; DNA Repair ; Fanconi Anemia/genetics ; Fanconi Anemia/metabolism ; Humans ; Recombination, Genetic
Chemical Substances	Cross-Linking Reagents ; DNA (9007-49-2)
Language	English
Publishing date	2009-12-17
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1000977-2
ISSN	1549-7798 ; 1381-3455 ; 1040-9238
ISSN (online)	1549-7798
ISSN	1381-3455 ; 1040-9238
DOI	10.3109/10409230903501819
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Article ; Online: Repair of laser-localized DNA interstrand cross-links in G1 phase mammalian cells.

Muniandy, Parameswary A / Thapa, Dennis / Thazhathveetil, Arun Kalliat / Liu, Su-Ting / Seidman, Michael M

The Journal of biological chemistry

2009 Volume 284, Issue 41, Page(s) 27908–27917

Abstract	Interstrand cross-links (ICLs) are absolute blocks to transcription and replication and can provoke genomic instability and cell death. Studies in bacteria define a two-stage repair scheme, the first involving recognition and incision on either side of the cross-link on one strand (unhooking), followed by recombinational repair or lesion bypass synthesis. The resultant monoadduct is removed in a second stage by nucleotide excision repair. In mammalian cells, there are multiple, but poorly defined, pathways, with much current attention on repair in S phase. However, many questions remain, including the efficiency of repair in the absence of replication, the factors involved in cross-link recognition, and the timing and demarcation of the first and second repair cycles. We have followed the repair of laser-localized lesions formed by psoralen (cross-links/monoadducts) and angelicin (only monoadducts) in mammalian cells. Both were repaired in G(1) phase by nucleotide excision repair-dependent pathways. Removal of psoralen adducts was blocked in XPC-deficient cells but occurred with wild type kinetics in cells deficient in DDB2 protein (XPE). XPC protein was rapidly recruited to psoralen adducts. However, accumulation of DDB2 was slow and XPC-dependent. Inhibition of repair DNA synthesis did not interfere with DDB2 recruitment to angelicin but eliminated recruitment to psoralen. Our results demonstrate an efficient ICL repair pathway in G(1) phase cells dependent on XPC, with entry of DDB2 only after repair synthesis that completes the first repair cycle. DDB2 accumulation at sites of cross-link repair is a marker for the start of the second repair cycle.
MeSH term(s)	Animals ; Cell Line ; Cross-Linking Reagents/pharmacology ; DNA/chemistry ; DNA/drug effects ; DNA/genetics ; DNA/metabolism ; DNA Adducts/chemistry ; DNA Adducts/metabolism ; DNA Damage ; DNA Repair ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Ficusin/pharmacology ; Furocoumarins/pharmacology ; G1 Phase/genetics ; Humans ; Intercalating Agents/pharmacology ; Lasers ; Molecular Structure
Chemical Substances	Cross-Linking Reagents ; DNA Adducts ; DNA-Binding Proteins ; Furocoumarins ; Intercalating Agents ; XPC protein, human (156533-34-5) ; DNA (9007-49-2) ; angelicin (CZZ080D7BD) ; Ficusin (KTZ7ZCN2EX)
Language	English
Publishing date	2009-08-14
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M109.029025
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Article ; Online: Distinct inhibitory effects on mTOR signaling by ethanol and INK128 in diffuse large B-cell lymphoma.

Mazan-Mamczarz, Krystyna / Peroutka, Raymond J / Steinhardt, James J / Gidoni, Moriah / Zhang, Yongqing / Lehrmann, Elin / Landon, Ari L / Dai, Bojie / Houng, Simone / Muniandy, Parameswary A / Efroni, Sol / Becker, Kevin G / Gartenhaus, Ronald B

Cell communication and signaling : CCS

2015 Volume 13, Page(s) 15

Abstract: Background: The mechanistic target of rapamycin, (mTOR) kinase plays a pivotal role in controlling critical cellular growth and survival pathways, and its aberrant induction is implicated in cancer pathogenesis. Therefore, suppression of active mTOR ... ...

Abstract	Background: The mechanistic target of rapamycin, (mTOR) kinase plays a pivotal role in controlling critical cellular growth and survival pathways, and its aberrant induction is implicated in cancer pathogenesis. Therefore, suppression of active mTOR signaling has been of great interest to researchers; several mTOR inhibitors have been discovered to date. Ethanol (EtOH), similar to pharmacologic mTOR inhibitors, has been shown to suppress the mTOR signaling pathway, though in a non-catalytic manner. Despite population studies showing that the consumption of EtOH has a protective effect against hematological malignancies, the mechanisms behind EtOH's modulation of mTOR activity in cells and its downstream consequences are largely unknown. Here we evaluated the effects of EtOH on the mTOR pathway, in comparison to the active-site mTOR inhibitor INK128, and compared translatome analysis of their downstream effects in diffuse large B-cell lymphoma (DLBCL). Results: Treatment of DLBCL cells with EtOH suppressed mTORC1 complex formation while increasing AKT phosphorylation and mTORC2 complex assembly. INK128 completely abrogated AKT phosphorylation without affecting the structure of mTORC1/2 complexes. Accordingly, EtOH less profoundly suppressed cap-dependent translation and global protein synthesis, compared to a remarkable inhibitory effect of INK128 treatment. Importantly, EtOH treatment induced the formation of stress granules, while INK128 suppressed their formation. Microarray analysis of polysomal RNA revealed that although both agents primarily affected cell growth and survival, EtOH and INK128 regulated the synthesis of mostly distinct genes involved in these processes. Though both EtOH and INK128 inhibited cell cycle, proliferation and autophagy, EtOH, in contrast to INK128, did not induce cell apoptosis. Conclusion: Given that EtOH, similar to pharmacologic mTOR inhibitors, inhibits mTOR signaling, we systematically explored the effect of EtOH and INK128 on mTOR signal transduction, components of the mTORC1/2 interaction and their downstream effectors in DLBCL malignancy. We found that EtOH partially inhibits mTOR signaling and protein translation, compared to INK128's complete mTOR inhibition. Translatome analysis of mTOR downstream target genes established that differential inhibition of mTOR by EtOH and INK128 distinctly modulates translation of specific subsets of mRNAs involved in cell growth and survival, leading to differential cellular response and survival.
MeSH term(s)	Autophagy/drug effects ; Autophagy/genetics ; Benzoxazoles/pharmacology ; Cell Cycle/drug effects ; Cell Cycle/genetics ; Cell Line, Tumor ; Central Nervous System Depressants/pharmacology ; Ethanol/pharmacology ; Humans ; Lymphoma, Large B-Cell, Diffuse/genetics ; Lymphoma, Large B-Cell, Diffuse/metabolism ; Lymphoma, Large B-Cell, Diffuse/pathology ; Mechanistic Target of Rapamycin Complex 1 ; Mechanistic Target of Rapamycin Complex 2 ; Multiprotein Complexes/genetics ; Multiprotein Complexes/metabolism ; Proto-Oncogene Proteins c-akt/genetics ; Proto-Oncogene Proteins c-akt/metabolism ; Pyrimidines/pharmacology ; Signal Transduction/drug effects ; Signal Transduction/genetics ; TOR Serine-Threonine Kinases/antagonists & inhibitors ; TOR Serine-Threonine Kinases/genetics ; TOR Serine-Threonine Kinases/metabolism
Chemical Substances	Benzoxazoles ; Central Nervous System Depressants ; Multiprotein Complexes ; Pyrimidines ; Ethanol (3K9958V90M) ; MTOR protein, human (EC 2.7.1.1) ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; Mechanistic Target of Rapamycin Complex 2 (EC 2.7.11.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; TOR Serine-Threonine Kinases (EC 2.7.11.1) ; sapanisertib (JGH0DF1U03)
Language	English
Publishing date	2015-03-01
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2126315-2
ISSN	1478-811X ; 1478-811X
ISSN (online)	1478-811X
ISSN	1478-811X
DOI	10.1186/s12964-015-0091-0
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Article ; Online: Fanconi Anemia Group J Helicase and MRE11 Nuclease Interact To Facilitate the DNA Damage Response

Suhasini, Avvaru N. / Sommers, Joshua A. / Muniandy, Parameswary A. / Coulombe, Yan / Cantor, Sharon B. / Masson, Jean-Yves / Seidman, Michael M. / Brosh, Robert M.

Molecular and Cellular Biology. 2013 June 1, v. 33, no. 11 p.2212-2227

2013

Abstract	FANCJ mutations are linked to Fanconi anemia (FA) and increase breast cancer risk. FANCJ encodes a DNA helicase implicated in homologous recombination (HR) repair of double-strand breaks (DSBs) and interstrand cross-links (ICLs), but its mechanism of action is not well understood. Here we show with live-cell imaging that FANCJ recruitment to laser-induced DSBs but not psoralen-induced ICLs is dependent on nuclease-active MRE11. FANCJ interacts directly with MRE11 and inhibits its exonuclease activity in a specific manner, suggesting that FANCJ regulates the MRE11 nuclease to facilitate DSB processing and appropriate end resection. Cells deficient in FANCJ and MRE11 show increased ionizing radiation (IR) resistance, reduced numbers of γH2AX and RAD51 foci, and elevated numbers of DNA-dependent protein kinase catalytic subunit foci, suggesting that HR is compromised and the nonhomologous end-joining (NHEJ) pathway is elicited to help cells cope with IR-induced strand breaks. Interplay between FANCJ and MRE11 ensures a normal response to IR-induced DSBs, whereas FANCJ involvement in ICL repair is regulated by MLH1 and the FA pathway. Our findings are discussed in light of the current model for HR repair.
Keywords	DNA damage ; DNA helicases ; Fanconi anemia ; breast neoplasms ; cell biology ; crosslinking ; homologous recombination ; mechanism of action ; models ; protein kinases ; protein subunits ; resection ; risk
Language	English
Dates of publication	2013-0601
Size	p. 2212-2227.
Publishing place	Taylor & Francis
Document type	Article ; Online
ZDB-ID	779397-2
ISSN	1098-5549 ; 0270-7306
ISSN (online)	1098-5549
ISSN	0270-7306
DOI	10.1128/MCB.01256-12
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: MNKs act as a regulatory switch for eIF4E1 and eIF4E3 driven mRNA translation in DLBCL.

Landon, Ari L / Muniandy, Parameswary A / Shetty, Amol C / Lehrmann, Elin / Volpon, Laurent / Houng, Simone / Zhang, Yongqing / Dai, Bojie / Peroutka, Raymond / Mazan-Mamczarz, Krystyna / Steinhardt, James / Mahurkar, Anup / Becker, Kevin G / Borden, Katherine L / Gartenhaus, Ronald B

Nature communications

2014 Volume 5, Page(s) 5413

Abstract: The phosphorylation of eIF4E1 at serine 209 by MNK1 or MNK2 has been shown to initiate oncogenic mRNA translation, a process that favours cancer development and maintenance. Here, we interrogate the MNK-eIF4E axis in diffuse large B-cell lymphoma (DLBCL) ...

Abstract	The phosphorylation of eIF4E1 at serine 209 by MNK1 or MNK2 has been shown to initiate oncogenic mRNA translation, a process that favours cancer development and maintenance. Here, we interrogate the MNK-eIF4E axis in diffuse large B-cell lymphoma (DLBCL) and show a distinct distribution of MNK1 and MNK2 in germinal centre B-cell (GCB) and activated B-cell (ABC) DLBCL. Despite displaying a differential distribution in GCB and ABC, both MNKs functionally complement each other to sustain cell survival. MNK inhibition ablates eIF4E1 phosphorylation and concurrently enhances eIF4E3 expression. Loss of MNK protein itself downregulates total eIF4E1 protein level by reducing eIF4E1 mRNA polysomal loading without affecting total mRNA level or stability. Enhanced eIF4E3 expression marginally suppresses eIF4E1-driven translation but exhibits a unique translatome that unveils a novel role for eIF4E3 in translation initiation. We propose that MNKs can modulate oncogenic translation by regulating eIF4E1-eIF4E3 levels and activity in DLBCL.
MeSH term(s)	Cell Line, Tumor ; Eukaryotic Initiation Factor-4E/genetics ; Eukaryotic Initiation Factor-4E/metabolism ; Humans ; Intracellular Signaling Peptides and Proteins/genetics ; Intracellular Signaling Peptides and Proteins/metabolism ; Lymphoma, Large B-Cell, Diffuse/enzymology ; Lymphoma, Large B-Cell, Diffuse/genetics ; Lymphoma, Large B-Cell, Diffuse/metabolism ; Phosphorylation ; Protein Biosynthesis ; Protein-Serine-Threonine Kinases/genetics ; Protein-Serine-Threonine Kinases/metabolism ; RNA, Messenger/genetics ; RNA, Messenger/metabolism
Chemical Substances	Eukaryotic Initiation Factor-4E ; Intracellular Signaling Peptides and Proteins ; RNA, Messenger ; eIF4E3 protein, human ; MKNK1 protein, human (EC 2.7.1.-) ; MKNK2 protein, human (EC 2.7.11.1) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2014-11-18
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/ncomms6413
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Article: Targeted gene knock in and sequence modulation mediated by a psoralen-linked triplex-forming oligonucleotide.

Majumdar, Alokes / Muniandy, Parameswary A / Liu, Jia / Liu, Ji-lan / Liu, Su-ting / Cuenoud, Bernard / Seidman, Michael M

The Journal of biological chemistry

2008 Volume 283, Issue 17, Page(s) 11244–11252

Abstract: Information from exogenous donor DNA can be introduced into the genome via homology-directed repair (HDR) pathways. These pathways are stimulated by double strand breaks and by DNA damage such as interstrand cross-links. We have employed triple helix- ... ...

Abstract	Information from exogenous donor DNA can be introduced into the genome via homology-directed repair (HDR) pathways. These pathways are stimulated by double strand breaks and by DNA damage such as interstrand cross-links. We have employed triple helix-forming oligonucleotides linked to psoralen (pso-TFO) to introduce a DNA interstrand cross-link at a specific site in the genome of living mammalian cells. Co-introduction of duplex DNA with target region homology resulted in precise knock in of the donor at frequencies 2-3 orders of magnitude greater than with donor alone. Knock-in was eliminated in cells deficient in ERCC1-XPF, which is involved in recombinational pathways as well as cross-link repair. Separately, single strand oligonucleotide donors (SSO) were co-introduced with the pso-TFO. These were 10-fold more active than the duplex knock-in donor. SSO efficacy was further elevated in cells deficient in ERCC1-XPF, in contrast to the duplex donor. Resected single strand ends have been implicated as critical intermediates in sequence modulation by SSO, as well as duplex donor knock in. We asked whether there would be a competition between the donor species for these ends if both were present with the pso-TFO. The frequency of duplex donor knock in was unaffected by a 100-fold molar excess of the SSO. The same result was obtained when the homing endonuclease I-SceI was used to initiate HDR at the target site. We conclude that the entry of double strand breaks into distinct HDR pathways is controlled by factors other than the nucleic acid partners in those pathways.
MeSH term(s)	Animals ; Base Sequence ; CHO Cells ; Cricetinae ; Cricetulus ; Cross-Linking Reagents/pharmacology ; DNA Damage ; DNA Repair ; Deoxyribonucleases, Type II Site-Specific/metabolism ; Endonucleases/metabolism ; Ficusin/pharmacology ; Hypoxanthine Phosphoribosyltransferase/metabolism ; Models, Biological ; Molecular Sequence Data ; Oligonucleotides/chemistry ; Oligonucleotides/metabolism ; Saccharomyces cerevisiae Proteins
Chemical Substances	Cross-Linking Reagents ; Oligonucleotides ; Saccharomyces cerevisiae Proteins ; Hypoxanthine Phosphoribosyltransferase (EC 2.4.2.8) ; Endonucleases (EC 3.1.-) ; SCEI protein, S cerevisiae (EC 3.1.21.-) ; Deoxyribonucleases, Type II Site-Specific (EC 3.1.21.4) ; Ficusin (KTZ7ZCN2EX)
Language	English
Publishing date	2008-02-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M800607200
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Article: Targeted Gene Knock In and Sequence Modulation Mediated by a Psoralen-linked Triplex-forming Oligonucleotide

Majumdar, Alokes / Muniandy, Parameswary A / Liu, Jia / Liu, Ji-lan / Liu, Su-ting / Cuenoud, Bernard / Seidman, Michael M

Journal of biological chemistry. 2008 Apr. 25, v. 283, no. 17

2008

Abstract	Information from exogenous donor DNA can be introduced into the genome via homology-directed repair (HDR) pathways. These pathways are stimulated by double strand breaks and by DNA damage such as interstrand cross-links. We have employed triple helix-forming oligonucleotides linked to psoralen (pso-TFO) to introduce a DNA interstrand cross-link at a specific site in the genome of living mammalian cells. Co-introduction of duplex DNA with target region homology resulted in precise knock in of the donor at frequencies 2-3 orders of magnitude greater than with donor alone. Knock-in was eliminated in cells deficient in ERCC1-XPF, which is involved in recombinational pathways as well as cross-link repair. Separately, single strand oligonucleotide donors (SSO) were co-introduced with the pso-TFO. These were 10-fold more active than the duplex knock-in donor. SSO efficacy was further elevated in cells deficient in ERCC1-XPF, in contrast to the duplex donor. Resected single strand ends have been implicated as critical intermediates in sequence modulation by SSO, as well as duplex donor knock in. We asked whether there would be a competition between the donor species for these ends if both were present with the pso-TFO. The frequency of duplex donor knock in was unaffected by a 100-fold molar excess of the SSO. The same result was obtained when the homing endonuclease I-SceI was used to initiate HDR at the target site. We conclude that the entry of double strand breaks into distinct HDR pathways is controlled by factors other than the nucleic acid partners in those pathways.
Language	English
Dates of publication	2008-0425
Size	p. 11244-11252.
Publishing place	American Society for Biochemistry and Molecular Biology
Document type	Article
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
Database	NAL-Catalogue (AGRICOLA)

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