Mammalian chromodomain proteins: their role in genome organisation and expression

Jones, David; Cowell, Ian G.; Singh, Prim B.

doi:10.1002/(sici)1521-1878(200002)22:2<124::aid-bies4>3.0.co;2-e

Cited by 265 publications

(178 citation statements)

References 83 publications

(116 reference statements)

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“…In addition to affecting transcriptional repression via chromatin remodeling (Jones et al ., 2000), the Chd3 protein contains two helicase domains that are present in various RecQ helicases and DNA repair proteins. Mutations in RecQ helicases and DNA repair proteins have been linked to premature aging phenotypes in humans as well as mutant mouse models (Martin & Oshima, 2000;de Boer et al ., 2002;Bachrati & Hickson, 2003).…”

Section: S Venkatachalam Department Of Biochemistry and Cellular Anmentioning

confidence: 99%

Complicating the role of p53 in aging

Gentry

Venkatachalam

2005

Aging Cell

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Recently, we described a p53 mutant mouse model (p53+/m mouse model) that presented a paradox, in which tumor free survival was coupled to reduced lifespan instead of extended lifespan (Tyner et al ., 2002). The p53+/m mice expressed a truncated p53 transcript attached to a leader sequence and showed a moderate increase in p53 activity. Based on this data we hypothesized that enhanced levels of p53 caused the early aging and cancer resistance phenotypes. This hypothesis was attractive as it indirectly implied a 'fine tuning' mechanism of tumor suppressor gene expression to maintain homeostasis at the organismal level (Campisi, 2002;Kirkwood, 2002). Our results also lent support to the evolutionary theory of antagonistic pleiotropy that predicts the deleterious effects of tumor-suppressor genes later in life (Williams, 1957). These observations notwithstanding, the p53+/m mouse model presented a caveat, in which tumor free survival was coupled to reduced lifespan instead of extended lifespan. Studies in model organisms have shown that enhanced resistance to oxidative stress correlates with increased longevity (Johnson et al ., 2002;Murakami et al ., 2003). The tumor suppressor functions of p53 overwhelmingly categorize it as a longevity assurance gene and suggest a synergistic effect on lifespan via tumor free survival of the organism. We show that there are 24 genes deleted in the p53+/m mouse model, complicating the role of p53 in aging and raising the possibility that the phenotypes while resembling 'premature aging-like' symptoms, may not be related to the physiological changes seen during normal aging processes.Along with the partial deletion of one of the p53 alleles, the p53+/m mouse had an upstream deletion that was originally not well defined due to the lack of mouse genome sequence data. This undefined deletion was a major drawback for our hypothesis, leaving open the possibility that the loss of other unidentified genes affected the p53+/m phenotypes. The importance of the upstream deletion was further underlined by the fact that we were unable to generate a p53 m/m mouse from p53+/m crosses even though p53 nullizygosity does not lead to embryonic lethality in mice (Donehower et al ., 1992). To determine the extent of the deletion, we blasted the leader sequence (initially cloned along with the truncated p53 transcript) to the Ensembl mouse genome sequence database and found it to be within the Rho guanine exchange factor 15 ( Arhgef15 ) gene approximately 0.6 Mb upstream of p53.To ascertain the fusion of the Argef15 and p53 alleles, we performed Southern blot assays with multiple restriction enzymes that were common to both the alleles. A schematic representation of the wild-type alleles of p53 and Argef15 is shown in Fig. 1 along with the restriction enzyme sites used for the characterization of the breakpoint present in the p53+/m mouse model. As shown in Fig. 2(a,b), the fusion of the two alleles leads to changes in the restriction fragment length polymorphism (RFLP) patterns of the wt and 'm' alle...

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Section: S Venkatachalam Department Of Biochemistry and Cellular Anmentioning

confidence: 99%

Complicating the role of p53 in aging

Gentry

Venkatachalam

2005

Aging Cell

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“…We therefore sought binding partners of ␤ 4c by two-hybrid screening of a cDNA library from the chicken's cochlear sensory epithelium. Thirtyone positive clones were isolated, all belonging to CHCBs (24), also termed HP1s (25). Members of the CHCB͞HP1 family contain a chromo domain and a chromo shadow domain (CSD; Fig.…”

Section: Resultsmentioning

confidence: 99%

Direct interaction with a nuclear protein and regulation of gene silencing by a variant of the Ca ²⁺ -channel β ₄ subunit

Hibino

Pironkova

Onwumere

et al. 2002

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

103

113

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The ␤ subunits of voltage-gated Ca 2؉ channels are known to be regulators of the channels' gating properties. Here we report a striking additional function of a ␤ subunit. Screening of chicken cochlear and brain cDNA libraries identified ␤4c, a short splice variant of the ␤4 subunit. Although ␤4c occurs together with the longer isoforms ␤4a or ␤4b in the brain, eye, heart, and lung, the cochlea expresses exclusively ␤4c. The association of ␤4c with the Ca 2؉ -channel ␣1 subunit has slight but significant effects on the kinetics of channel activation and inactivation. Yeast two-hybrid and biochemical assays revealed that ␤4c interacts directly with the chromo shadow domain of chromobox protein 2͞heterochromatin protein 1␥ (CHCB2͞HP1␥), a nuclear protein involved in gene silencing and transcriptional regulation. Coexpression of this protein specifically recruits ␤4c to the nuclei of mammalian cells. Furthermore, ␤4c but not ␤4a dramatically attenuates the genesilencing activity of chromobox protein 2͞heterochromatin protein 1␥. The ␤4c subunit is therefore a multifunctional protein that not only constitutes a portion of the Ca 2؉ channel but also regulates gene transcription.

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“…The chromoshadow domain shares sequence homology with the chromodomain that lies near the N terminus of HP1. Chromodomains have been identified in many factors that affect gene expression and chromatin structure (39), whereas the chromoshadow domain is unique to HP1 (40). To define further the region of HP1␥ required for interaction with hTAF II 130, we performed binding studies by using an in vitro-translated and -radiolabeled hTAF II 130 polypeptide fragment that had been used as bait in the yeast two-hybrid screen (Fig.…”

Section: Identification Of An Interaction Between Htafii130 and Hp1mentioning

confidence: 99%

Isoform-specific interaction of HP1 with human TAF _II 130

Vassallo

Tanese

2002

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

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The general transcription factor TFIID facilitates recruitment of the transcription machinery to gene promoters and regulates initiation of transcription by RNA polymerase II. hTAFII130, a component of TFIID, interacts with and serves as a coactivator for multiple transcriptional regulatory proteins, including Sp1 and CREB. A yeast two-hybrid screen has identified an interaction between hTAFII130 and heterochromatin protein 1 (HP1), a chromatinassociated protein whose function has been implicated in gene silencing. We find that hTAFII130 associates with HP1 in an isoformspecific manner: HP1␣ and HP1␥ bind to hTAFII130, but not HP1␤. In addition, we show that endogenous hTAFII130 and components of TFIID in HeLa nuclear extracts associate with glutathione Stransferase-HP1␣ and -HP1␥. hTAF II 130 possesses a pentapeptide HP1-binding motif, and mutation of the hTAFII130 HP1 box compromises the interaction of hTAFII130 with HP1. We demonstrate that Gal4-HP1 proteins interfere with hTAFII130-mediated activation of transcription. Our results suggest that HP1␣ and HP1␥ associate with hTAFII130 to mediate repression of transcription, supporting a new model of transcriptional repression involving a specific interaction between a component of TFIID and chromatin.T he general transcription factor TFIID, through the activities of its composite TATA-binding protein (TBP) and TBPassociated factors (TAF II s), plays a central role in the regulation of transcription by RNA polymerase II (reviewed in refs. 1-4). TAF II s participate in transcription by serving as molecular integrators of signals mediated by site-specific transcription factors, assisting in promoter recognition, enzymatically modifying target proteins, and facilitating the nucleation of the preinitiation complex formation. A plethora of biochemical and genetic data support the notion that TAF II s function at the interface between gene-specific transcriptional regulators and general transcription machinery.Human TFIID, composed of TBP and 13 associated TAF II s, is required for activator-dependent transcription in vitro. hTAF II 130 and its Drosophila homologue dTAF II 110 directly contact the glutamine-rich activation domains of Sp1 and function as Sp1's coactivator (5-7). dTAF II 110 and hTAF II 130 also interact with the Q2 activation domain of the cAMP-responsive transcription factor CREB and mediates its activation function (7-9). In addition, hTAF II 130 increases transcriptional activation by the retinoic acid, vitamin D3, and thyroid hormone receptors without directly contacting their activation domains (10).We have mapped the domains of hTAF II 130 that interact with Sp1 and CREB to the central glutamine-rich regions (refs. 11 and 12, Fig. 1A Modulation of chromatin structure plays a fundamental role in gene expression because transcription factors must contend with the nucleosomes, which are generally inhibitory to transcription. Genetic and biochemical approaches have led to the discovery of multiple transcription factor complexes that are thought to a...

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Mammalian chromodomain proteins: their role in genome organisation and expression

Cited by 265 publications

References 83 publications

Complicating the role of p53 in aging

Complicating the role of p53 in aging

Direct interaction with a nuclear protein and regulation of gene silencing by a variant of the Ca ²⁺ -channel β ₄ subunit

Isoform-specific interaction of HP1 with human TAF _II 130

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Mammalian chromodomain proteins: their role in genome organisation and expression

Cited by 265 publications

References 83 publications

Complicating the role of p53 in aging

Complicating the role of p53 in aging

Direct interaction with a nuclear protein and regulation of gene silencing by a variant of the Ca 2+ -channel β 4 subunit

Isoform-specific interaction of HP1 with human TAF II 130

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Direct interaction with a nuclear protein and regulation of gene silencing by a variant of the Ca ²⁺ -channel β ₄ subunit

Isoform-specific interaction of HP1 with human TAF _II 130