“…The CENP-A binding domain of HJURP is conserved from budding yeast to humans which is essential for the deposition of new CENP-A [28–30]. Drosophila has evolved a non-homologous CENP-A chaperone, CAL1 [31,32], and some organisms, including C. elegans lack a clear HJURP or CAL1 homolog, suggesting these organisms have evolved different, but potentially related mechanisms to establish centromeric chromatin.…”
Section: Pre-nucleosomal Posttranslational Modification Of Centromerimentioning
Accurate chromosome segregation is critical to ensure the faithful inheritance of the genome during cell division. Human chromosomes distinguish the location of the centromere from general chromatin by the selective assembly of CENP-A containing nucleosomes at the active centromere. The location of centromeres in most higher eukaryotes is determined epigenetically, independent of DNA sequence. CENP-A containing centromeric chromatin provides the foundation for assembly of the kinetochore that mediates chromosome attachment to the microtubule spindle and controls cell cycle progression in mitosis. Here we review recent work demonstrating the role of posttranslational modifications on centromere function and CENP-A inheritance via the direct modification of the CENP-A nucleosome and pre-nucleosomal complexes, the modification of the CENP-A deposition machinery and the modification of histones within existing centromeres.
“…The CENP-A binding domain of HJURP is conserved from budding yeast to humans which is essential for the deposition of new CENP-A [28–30]. Drosophila has evolved a non-homologous CENP-A chaperone, CAL1 [31,32], and some organisms, including C. elegans lack a clear HJURP or CAL1 homolog, suggesting these organisms have evolved different, but potentially related mechanisms to establish centromeric chromatin.…”
Section: Pre-nucleosomal Posttranslational Modification Of Centromerimentioning
Accurate chromosome segregation is critical to ensure the faithful inheritance of the genome during cell division. Human chromosomes distinguish the location of the centromere from general chromatin by the selective assembly of CENP-A containing nucleosomes at the active centromere. The location of centromeres in most higher eukaryotes is determined epigenetically, independent of DNA sequence. CENP-A containing centromeric chromatin provides the foundation for assembly of the kinetochore that mediates chromosome attachment to the microtubule spindle and controls cell cycle progression in mitosis. Here we review recent work demonstrating the role of posttranslational modifications on centromere function and CENP-A inheritance via the direct modification of the CENP-A nucleosome and pre-nucleosomal complexes, the modification of the CENP-A deposition machinery and the modification of histones within existing centromeres.
“…During DNA replication in human cells, no new CENP-A deposition occurs (Jansen et al, 2007) and histone H3.3, and H3.1 are deposited as place-holders (Dunleavy et al, 2011). CENP-A deposition occurs during or after mitosis in Drosophila and humans, respectively (Hemmerich et al, 2008; Jansen et al, 2007; Mellone et al, 2011; Schuh et al, 2007) and is mediated by specialized histone chaperones known as Scm3 in fungi (Camahort et al, 2007; Pidoux et al, 2009; Stoler et al, 2007), HJURP in tetrapods (Barnhart et al, 2011; Bernad et al, 2011; Dunleavy et al, 2009; Foltz et al, 2009; Sanchez-Pulido et al, 2009; Shuaib et al, 2010), and CAL1 in flies (Chen et al, 2014). Each of these chaperones has been shown to selectively bind CENP-A, and not canonical H3, and to mediate the formation of CENP-A nucleosomes in vitro .…”
Summary
Centromeres are essential chromosomal structures that mediate accurate chromosome segregation during cell division. Centromeres are specified epigenetically by the heritable incorporation of the centromeric histone H3 variant, CENP-A. While many of the primary factors that mediate centromeric deposition of CENP-A are known, the chromatin and DNA requirements in this process have remained elusive. Here, we uncover a role for transcription in Drosophila CENP-A deposition. Using an inducible ectopic centromere system that uncouples CENP-A deposition from endogenous centromere function and cell-cycle progression, we demonstrate that CENP-A assembly by its loading factor, CAL1, requires RNAPII-mediated transcription of the underlying DNA. This transcription depends on the novel CAL1 binding partner FACT, but not on CENP-A incorporation. Our work establishes RNAPII passage as a key step in chaperone-mediated CENP-A chromatin establishment and propagation.
“…Ubiquitylation of dCENP-A CID is distinguished by the fact that the E3 ligase CUL3/RDX1 complex directly interacts with the functional homolog of HJURP in flies, called CAL1, which serves as an adaptor for the enzymatic reaction (Bade et al 2014; Chen et al 2014; Erhardt et al 2008). CAL1 itself does not undergo ubiquitylation; nonetheless, both CAL1 and dCENP-A CID are stabilized by the CUL3/RDX complex, and loss of RDX leads to fragmented chromosomes and perturbs centromere maintenance.…”
Section: Diversity Of Cenp-a Modifications Across Speciesmentioning
Centromeres are specialized chromosome domain that serve as the site for kinetochore assembly and microtubule attachment during cell division, to ensure proper segregation of chromosomes. In higher eukaryotes, the identity of active centromeres is marked by the presence of CENP-A (centromeric protein-A), a histone H3 variant. CENP-A forms a centromere-specific nucleosome that acts as a foundation for centromere assembly and function. The posttranslational modification (PTM) of histone proteins is a major mechanism regulating the function of chromatin. While a few CENP-A site-specific modifications are shared with histone H3, the majority are specific to CENP-A-containing nucleosomes, indicating that modification of these residues contribute to centromere-specific function. CENP-A undergoes posttranslational modifications including phosphorylation, acetylation, methylation, and ubiquitylation. Work from many laboratories have uncovered the importance of these CENP-A modifications in its deposition at centromeres, protein stability, and recruitment of the CCAN (constitutive centromere-associated network). Here, we discuss the PTMs of CENP-A and their biological relevance.
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