G4 DNA Binding by LR1 and Its Subunits, Nucleolin and hnRNP D, A Role for G-G pairing in Immunoglobulin Switch Recombination

Dempsey, Laurie A; Sun, Hui; Hanakahi, Leslyn A.; Maizels, Nancy

doi:10.1074/jbc.274.2.1066

Cited by 166 publications

(124 citation statements)

References 49 publications

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“…Biologically, G-rich DNA have been identified in three distinct regions of the genome (telomeres, rDNA, and switch-recombination regions) (Dempsey et al 1999). Our findings suggest a fourth region, the pericentromeric regions of human chromosomes, where these sequences define the boundaries of recently duplicated genomic segments.…”

Section: Genome Research 1053mentioning

confidence: 81%

CAGGG Repeats and the Pericentromeric Duplication of the Hominoid Genome

Eichler¹,

Archidiacono²,

Rocchi³

1999

Genome Res.

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Gene duplication is one of the primary forces of evolutionary change. We present data from three different pericentromeric regions of human chromosomes, which indicate that such regions of the genome have been sites of recent genomic duplication. This form of duplication has involved the evolutionary movement of segments of genomic material, including both intronic and exonic sequence, from diverse regions of the genome toward the pericentromeric regions. Sequence analyses of the target sites of duplication have identified a novel class of interspersed GC-rich repeats located precisely at the boundaries of duplication. Estimates of the evolutionary age of these duplications indicate that they have occurred between 10 and 25 mya. In contrast, comparative analyses confirm that the GC-rich pericentromeric repeats have existed within the pericentromeric regions of primate chromosomes before the divergence of the cercopithecoid and hominoid lineages (∼30 mya). These data provide molecular evidence for considerable interchromosomal duplication of genic segments during the evolution of the hominoid genome and strongly implicate GC-rich repeat elements as playing a direct role in the pericentromeric localization of these events Genome evolution is dependent on the processes of single-base-pair mutation and gene duplication. Duplication of a gene followed by mutation is responsible for the emergence of new genes with specialized functions in an evolving species. Two distinct molecular mechanisms of gene duplication are generally recognized. Tandem duplication of an ancestral gene, vis-à-vis processes of unequal crossover, produces a clustered family of related genes (Smith 1976). In contrast, whole-genome duplication (polyploidy) followed by chromosomal rearrangement and the re-establishment of the disomic state has been proposed as a mechanism for the interchromosomal duplication of large segments of a genome (Ohno 1970). The latter model, put forward originally by Susumu Ohno, explains observations of conserved genic synteny among nonhomologous chromosomes. Because of the genetic consequences of polyploidy, such events, although important in the early expansion of eukaryotic genomes, are rare and ancient (Ohno 1993;Wolfe and Shields 1997). Within the vertebrate lineage, for example, the last tetraploidization event leading to genome duplication is estimated to have occurred >400 mya (Lundin 1993). If polyploidy were the only model by which entire genes could be duplicated among nonhomologous chromosomes, it would then follow that interchromosomal paralogs of recent origin would be unexpected.Recent analyses of data from the Human Genome Project suggest a third form of genomic duplication, which is mechanistically distinct from polyploidy and tandem duplication models of genome evolution. Several independent reports indicate that genic segments, ranging in length from 5 kb to 30 kb, possess duplicate copies within the pericentromeric regions of human autosomes (Borden et

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Section: Genome Research 1053mentioning

confidence: 81%

CAGGG Repeats and the Pericentromeric Duplication of the Hominoid Genome

Eichler¹,

Archidiacono²,

Rocchi³

1999

Genome Res.

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“…On the other hand, previous studies of endogenous S regions have necessarily viewed S regions as large DNA fragments, with no ability to readily dissect function of their component motifs. While R-loop-forming ability and the density of AGCT and related motifs may be major contributors to targeting CSR, Ig isotype-specific elements and structures [inverted repeats and stem-loop structures (29)], G4 quartets (30), and other factors (e.g., transcription levels, location, etc.) also have been argued to contribute to differential CSR targeting (25).…”

Section: Discussionmentioning

confidence: 99%

Influence of switch region length on immunoglobulin class switch recombination

Zarrin

Tian

Wang

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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The class and effector functions of antibodies are modulated through the process of Ig heavy chain class switch recombination (CSR). CSR occurs between switch (S) regions that lie upstream of the various Ig heavy chain constant region exons. Molecular analyses of S-region functions have been hampered by their large size and repetitive nature. To test potential relationships between S-region size and efficiency of CSR, we generated normal B lymphocytes in which the 12-kb S region flanking the C␥1 exons (S␥1) was replaced with synthetic or endogenous S regions of various lengths. Replacement of S␥1 with 1-and 2-kb synthetic sequences representing the S␥1 core repeats or a 4-kb portion of the core endogenous S␥1 region supported CSR frequencies that directly correlated with S-region length. These findings indicate that Sregion size is an important factor in determining endogenous CSR efficiency. Moreover, these results also will allow the development of a systematic system to test the function of various S-region motifs by replacing endogenous S regions with synthetic S regions controlled for size effects.IgH switch region ͉ activation-induced deaminase ͉ synthetic switch region ͉ IgG1

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“…Nucleolin has high affinity for AS1411, in agreement with the strong binding of nucleolin to G-quadruplex DNA sequences. 133,134 AS1411 may directly inhibit the RNA-binding activity of nucleolin, as AS1411 reduced nucleolin binding to BCL2 mRNA resulting in BCL2 mRNA destabilization, decreased Bcl-2 protein levels, apoptotic death of cultured human breast cancer cells, and inhibition of cancer cell growth in xenografts. 135,136 Other effects of AS1411 include the inhibition of NFκB via the formation of a complex containing nucleolin and the NFκB essential modulator (NEMO).…”

Section: Targeting Nucleolin For Therapymentioning

confidence: 99%