Aberrant replication timing induces defective chromosome condensation in Drosophila ORC2 mutants

Shen

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

et al. 2010

130

146

The origin recognition complex (ORC) is a DNA replication initiator protein also known to be involved in diverse cellular functions including gene silencing, sister chromatid cohesion, telomere biology, heterochromatin localization, centromere and centrosome activity, and cytokinesis. We show that, in human cells, multiple ORC subunits associate with hetereochromatin protein 1 (HP1) α-and HP1β-containing heterochromatic foci. Fluorescent bleaching studies indicate that multiple subcomplexes of ORC exist at heterochromatin, with Orc1 stably associating with heterochromatin in G1 phase, whereas other ORC subunits have transient interactions throughout the cell-division cycle. Both Orc1 and Orc3 directly bind to HP1α, and two domains of Orc3, a coiled-coil domain and a mod-interacting region domain, can independently bind to HP1α; however, both are essential for in vivo localization of Orc3 to heterochromatic foci. Direct binding of both Orc1 and Orc3 to HP1 suggests that, after the degradation of Orc1 at the G1/S boundary, Orc3 facilitates assembly of ORC/HP1 proteins to chromatin. Although depletion of Orc2 and Orc3 subunits by siRNA caused loss of HP1α association to heterochromatin, loss of Orc1 and Orc5 caused aberrant HP1α distribution only to pericentric heterochromatin-surrounding nucleoli. Depletion of HP1α from human cells also shows loss of Orc2 binding to heterochromatin, suggesting that ORC and HP1 proteins are mutually required for each other to bind to heterochromatin. Similar to HP1α-depleted cells, Orc2 and Orc3 siRNA-treated cells also show loss of compaction at satellite repeats, suggesting that ORC together with HP1 proteins may be involved in organizing higherorder chromatin structure and centromere function.centromere | origin recognition complex | pericentric heterochromatin | chromatin structure

mentioning

confidence: 99%

Human origin recognition complex is essential for HP1 binding to chromatin and heterochromatin organization

Shen

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

et al. 2010

130

146

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

“…Thus, ORC1 participates in repression of yeast HMR and HML silent mating type loci (13), and human aldolase B (14) and c-Myc genes (15). Mutations of several ORC subunits in multicellular organisms cause pleiotropic phenotypes including chromosomal abnormalities, cell cycle arrest or zygotic lethality (16)(17)(18).…”

mentioning

confidence: 99%

Arabidopsis ORC1 is a PHD-containing H3K4me3 effector that regulates transcription

Sánchez

Gutiérrez

2009

Control of gene expression depends on a complex and delicate balance of various posttranslational modifications of histones. However, the relevance of specific combinations of histone modifications is not fully defined. Downstream effector proteins recognize particular histone modifications and transduce this information into gene expression patterns. Methylation of histone H3 at lysine 4 (H3K4me) is a landmark of gene expression control in eukaryotes. Its recognition depends on the presence in the effector protein of a motif termed plant homeodomain (PHD) that specifically binds to H3K4me3. Here, we establish that Arabidopsis ORC1, the large subunit of the origin recognition complex involved in defining origins of DNA replication, functions as a transcriptional activator of a subset of genes, the promoters of which are preferentially bound by ORC1. Arabidopsis ORC1 contains a PHD and binds to H3K4me3. In addition to H4 acetylation, ORC1 binding correlates with increased H4K20me3 in the proximal promoter region of ORC1 targets. This suggests that H4K20me3, unlike in animal cells, is associated with transcriptional activation in Arabidopsis. Thus, our data provide a molecular basis for the opposite role of ORC1 in transcriptional activation in plants and repression in animals. Since only ORC1 proteins of plant species contain a PHD, we propose that plant ORC1 constitutes a novel class of H3K4me3 effector proteins characteristic of the plant kingdom.cell cycle transcription ͉ histone H3 lysine 4 methylation ͉ ORC1 DNA replication ͉ plant homeodomain

“…This leads to the cell cycle arrest during mitosis, which is accompanied by the abnormal chromosome condensation, chromosome fragmentation, and a partial absence of cohesion between sister chromatids. Similar cell phenotypes were described in Drosophila mutants for ORC5, MCM4, and other replication factors [83]. A relationship between the ORCA-ORC complex and replication timing has been detected in human cell culture [50,52].…”

Section: Replication Timingmentioning

confidence: 53%

“…Obviously, ORC exerts its effects on the replication timing of different chromatin regions. In D. melanogaster , a mutation in the Orc2 gene impairs euchromatic replication, specifically, the time of replication is shifted and euchromatin duplicates after heterochromatin [83]. In this background, replication also remains incomplete at certain regions [83].…”

Section: Replication Timingmentioning

confidence: 99%

“…In D. melanogaster , a mutation in the Orc2 gene impairs euchromatic replication, specifically, the time of replication is shifted and euchromatin duplicates after heterochromatin [83]. In this background, replication also remains incomplete at certain regions [83]. This leads to the cell cycle arrest during mitosis, which is accompanied by the abnormal chromosome condensation, chromosome fragmentation, and a partial absence of cohesion between sister chromatids.…”

Section: Replication Timingmentioning

confidence: 99%

See 1 more Smart Citation

Nonreplicative functions of the origin recognition complex

Popova

Brechalov

Георгиева

et al. 2018

Nucleus

Origin recognition complex (ORC), a heteromeric six-subunit complex, is the central component of the eukaryotic pre-replication complex. Recent data from yeast, frogs, flies and mammals present compelling evidence that ORC and its individual subunits have nonreplicative functions as well. The majority of these functions, such as heterochromatin formation, chromosome condensation, and segregation are dependent on ORC-DNA interactions. Furthermore, ORC is involved in the control of cell division via its participation in centrosome duplication and cytokinesis. Recent findings have also demonstrated a direct interaction between ORC and mRNPs and highlighted an essential role of ORC in mRNA nuclear export. Along with the growth of evolutionary complexity of organisms, ORC complex functions become more elaborate and new functions of the ORC sub-complexes and individual subunits have emerged.