Molecular Implications of Evolutionary Differences in CHD Double Chromodomains

Flanagan, John F.; Blus, Bartlomiej J.; Kim, Dae-Sung; Clines, Katrina L.; Rastinejad, Fraydoon; Khorasanizadeh, Sepideh

doi:10.1016/j.jmb.2007.03.024

Cited by 54 publications

(76 citation statements)

References 47 publications

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“…Recently, we reported substantial evolutionary differences in the binding abilities of CHD double chromodomains that correlate with limited amino acid changes (44). These observations are consistent with complex control mechanisms associated with signaling enzymatic function in higher eukaryotes (45).…”

Section: Discussionsupporting

confidence: 82%

Specificity of the Chromodomain Y Chromosome Family of Chromodomains for Lysine-methylated ARK(S/T) Motifs

Fischle

Franz

Jacobs

et al. 2008

Journal of Biological Chemistry

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107

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Previous studies have shown two homologous chromodomain modules in the HP1 and Polycomb proteins exhibit discriminatory binding to related methyllysine residues (embedded in ARKS motifs) of the histone H3 tail. Methylated ARK(S/T) motifs have recently been identified in other chromatin factors (e.g. linker histone H1.4 and lysine methyltransferase G9a). These are thought to function as peripheral docking sites for the HP1 chromodomain. In vertebrates, HP1-like chromodomains are also present in the chromodomain Y chromosome (CDY) family of proteins adjacent to a putative catalytic motif. The human genome encodes three CDY family proteins, CDY, CDYL, and CDYL2. These have putative functions ranging from establishment of histone H4 acetylation during spermiogenesis to regulation of transcription co-repressor complexes. To delineate the biochemical functions of the CDY family chromodomains, we analyzed their specificity of methyllysine recognition. We detected substantial differences among these factors. The CDY chromodomain exhibits discriminatory binding to lysinemethylated ARK(S/T) motifs, whereas the CDYL2 chromodomain binds with comparable strength to multiple ARK(S/T) motifs. Interestingly, subtle amino acid changes in the CDYL chromodomain prohibit such binding interactions in vitro and in vivo. However, point mutations can rescue binding. In support of the in vitro binding properties of the chromodomains, the full-length CDY family proteins exhibit substantial variability in chromatin localization. Our studies underscore the significance of subtle sequence differences in a conserved signaling module for diverse epigenetic regulatory pathways.The human Y chromosome has been thoroughly sequenced and compared with partially sequenced Y chromosomes of chimpanzee and mouse (1-3). The Y chromosomes are believed to be enriched in genes essential for spermatogenesis and testis development. Interstitial Y chromosome deletions are associated with spermatogenic failure and male infertility (1,4,5). One gene that is present in multiple copies on the human Y chromosome is CDY, 5 which exhibits testis-specific expression (1). Interestingly, the mouse Y chromosome does not encode CDY, suggesting a developmentally advanced usage of CDY in primates (3).The human CDY gene seems to be derived from the autosomal homologs CDYL or CDYL2 (Fig. 1, A and B) (6). CDYL is ubiquitously expressed, whereas CDYL2 exhibits selective expression in tissues of testis, prostate, spleen, and leukocytes (6). The mouse genome also encodes related CDYL and CDYL2 genes (Fig. 1B). The presence of CDY-like genes appears to be a hallmark of echinoderm and vertebrate genomes. In sea urchin and chicken genomes we found only one CDY-like gene that corresponds to mammalian CDYL2 (Fig. 1B).CDY family proteins have two conserved domains implicated in histone modification and recognition; that is, a chromodomain followed by an enoyl-coenzyme A hydratase/isomerase (ECH) putative catalytic domain (Fig. 1A). Previously, it was shown that the chromodomain of hum...

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Section: Discussionsupporting

confidence: 82%

Specificity of the Chromodomain Y Chromosome Family of Chromodomains for Lysine-methylated ARK(S/T) Motifs

Fischle

Franz

Jacobs

et al. 2008

Journal of Biological Chemistry

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107

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“…However, structural work on yeast Chd1 suggests that it does not bind methylated lysines (Flanagan et al 2007). We believe that Set2 and Chd1 function in separate pathways, as the two mutations show additivity in suppressing the HUsensitive phenotypes of yFACT mutants and had different or even opposite effects in assays described here.…”

Section: Discussionmentioning

confidence: 73%

“…Additionally, set2 shows genetic interactions with genes implicated in elongation (Krogan et al 2003;Li et al 2003;Biswas et al 2006). CHD1 encodes an ATP-dependent chromatin remodeler (Tran et al 2000) with a double chromodomain (Flanagan et al 2007) and a Myb-related DNA-binding domain (Woodage et al 1997). Like Set2, Chd1 associates with transcribed regions of genes (Simic et al 2003) and shows physical and genetic interactions with elongation factors (Kelley et al 1999;Tsukiyamaet al 1999;Krogan et al 2002;Simic et al 2003;Biswas et al 2007).…”

mentioning

confidence: 99%

A Role for Chd1 and Set2 in Negatively Regulating DNA Replication in Saccharomyces cerevisiae

Biswas¹,

Takahata²,

Hua

et al. 2008

Genetics

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Chromatin-modifying factors regulate both transcription and DNA replication. The yFACT chromatinreorganizing complex is involved in both processes, and the sensitivity of some yFACT mutants to the replication inhibitor hydroxyurea (HU) is one indication of a replication role. This HU sensitivity can be suppressed by disruptions of the SET2 or CHD1 genes, encoding a histone H3(K36) methyltransferase and a chromatin remodeling factor, respectively. The additive effect of set2 and chd1 mutations in suppressing the HU sensitivity of yFACT mutants suggests that these two factors function in separate pathways. The HU suppression is not an indirect effect of altered regulation of ribonucleotide reductase induced by HU. set2 and chd1 mutations also suppress the HU sensitivity of mutations in other genes involved in DNA replication, including CDC2, CTF4, ORC2, and MEC1. Additionally, a chd1 mutation can suppress the lethality normally caused by disruption of either MEC1 or RAD53 DNA damage checkpoint genes, as well as the lethality seen when a mec1 sml1 mutant is exposed to low levels of HU. The pob3 defect in S-phase progression is suppressed by set2 or chd1 mutations, suggesting that Set2 and Chd1 have specific roles in negatively regulating DNA replication.

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“…32 In contrast, other CHD family members such as CHD3 and CHD4 have been described as expression repressors. 33,34 These data, together with the reported role of CHD2 in myogenic differentiation, 35 suggest that the putative effects of CHD2 mutation in CLL could be related to the regulation of active gene transcription. We therefore set out to assess the distribution of wild-type and mutated CHD2 proteins in the cell nucleus and their association with transcriptionally active chromatin.…”

Section: Resultsmentioning

confidence: 87%

Mutations in CHD2 cause defective association with active chromatin in chronic lymphocytic leukemia

Rodrı́guez

Bretones

Quesada

et al. 2015

Blood

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Key Points• Somatic mutations alter nuclear distribution and association of CHD2 with actively transcribed genes in CLL.• CHD2 is the most frequently mutated CLL driver in the IGHV-mutated prognostic subgroup.Great progress has recently been achieved in the understanding of the genomic alterations driving chronic lymphocytic leukemia (CLL). Nevertheless, the specific molecular mechanisms governing chromatin remodeling in CLL are unknown. Here we report the genetic and functional characterization of somatic mutations affecting the chromatin remodeler CHD2, one of the most frequently mutated genes in CLL (5.3%) and in monoclonal B lymphocytosis (MBL, 7%), a B-cell expansion that can evolve to CLL. Most of the mutations affecting CHD2, identified by whole-exome sequencing of 456 CLL and 43 MBL patients, are either truncating or affect conserved residues in functional domains, thus supporting a putative role for CHD2 as a tumor suppressor gene. CHD2 mutants show altered nuclear distribution, and a chromodomain helicase DNA binding protein 2 (CHD2) mutant affected in its DNA-binding domain exhibits defective association with active chromatin. Clinicobiological analyses show that most CLL patients carrying CHD2 mutations also present mutated immunoglobulin heavy chain variable region genes (IGHVs), being the most frequently mutated gene in this prognostic subgroup. This is the first study providing functional evidence supporting CHD2 as a cancer driver and opens the way to further studies of the role of this chromatin remodeler in CLL. (Blood. 2015;126(2):195-202) IntroductionChronic lymphocytic leukemia (CLL) is the most prevalent B-cell neoplasm in Western adults. CLL shows a remarkably heterogeneous course, with some patients presenting an indolent disease and normal life span, whereas others suffer from a dismal prognosis. [1][2][3] In general, disease outcome correlates with the immunoglobulin heavy chain variable region genes (IGHV) mutational status of tumor lymphocytes, 4,5 but also with other biological features including chromosomal aberrations and the expression of CLL-specific biomarkers. [5][6][7][8] Recently, whole-genome sequencing-based reports have uncovered NOTCH1, MYD88, and XPO1 as recurrently mutated CLL drivers.9 Additionally, whole-exome sequencing approaches have identified the splicing factor SF3B1 10-13 and the shelterin complex member POT1 14 as CLL drivers associated with unfavorable prognosis. Also, mutations in sucrose isomaltase have been proposed to play a role in the CLL leukemogenic metabolic switch. 15 Moreover, clonal evolution events in CLL have been delineated, pointing to the presence of subclonal driver mutations as a relevant prognostic factor in this disease.16 Notably, mutations in many of the previously described driver genes, as well as in BRAF, EGR2, and NFKBIE, can be detected in pluripotent hematopoietic progenitor cells, indicating that founding CLL mutations appear as very early evolutionary events.17 These genomic studies have been extended by comprehensive transc...

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Molecular Implications of Evolutionary Differences in CHD Double Chromodomains

Cited by 54 publications

References 47 publications

Specificity of the Chromodomain Y Chromosome Family of Chromodomains for Lysine-methylated ARK(S/T) Motifs

Specificity of the Chromodomain Y Chromosome Family of Chromodomains for Lysine-methylated ARK(S/T) Motifs

A Role for Chd1 and Set2 in Negatively Regulating DNA Replication in Saccharomyces cerevisiae

Mutations in CHD2 cause defective association with active chromatin in chronic lymphocytic leukemia

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