Centromere-Specific Assembly of CENP-A Nucleosomes Is Mediated by HJURP

Abstract

Summary The centromere is responsible for accurate chromosome segregation. Mammalian centromeres are specified epigenetically, with all active centromeres containing centromere specific chromatin in which CENP-A replaces histone H3 within the nucleosome. The proteins responsible for assembly of human CENP-A into centromeric nucleosomes during the G1 phase of the cell cycle are now identified to be distinct from the chromatin assembly factors that load other histone H3 variants. Prenucleosomal CENP-A is complexed with histone H4, nucleophosmin 1 and HJURP. Recruitment of new CENP-A into nucleosomes at replicated centromeres is dependent on HJURP. Recognition by HJURP is mediated through the centromere targeting domain (CATD) of CENP-A, a region that induces a unique conformational rigidity to both the subnucleosomal CENP-A heterotetramer and the corresponding assembled nucleosome. We propose HJURP to be a cell cycle regulated CENP-A specific histone chaperone required for centromeric chromatin assembly.

Epigenetic engineering: histone H3K9 acetylation is compatible with kinetochore structure and function

“…It is known that RNA polymerase can interact with factors transiently destabilizing nucleosomes to promote elongation through chromatin (Selth et al, 2010;Workman, 2006). Therefore, excessive centromeric polymerase activity might cause specific loss of CENP-A as a consequence of a limiting pool of available CENP-A or as a result of its association with histone chaperones, such as HJURP (Dunleavy et al, 2009;Foltz et al, 2009).…”

Nucleolin and nucleophosmin: nucleolar proteins with multiple functions in DNA repair

“…The histone chaperone activities of NCL and NPM1 have been known for at least 10 years (Angelov et al 2006;Okuwaki et al 2001), as have their ability to regulate activity on Pol II-transcribed loci (Angelov et al 2006). However, the widespread importance of these activities are only now becoming clear with the observations of their contribution to diverse processes including rDNA repeat silencing (Cong et al 2012), centrosome stability (Foltz et al 2009) and, most recently, chromatin remodeling during HR and/or NHEJ (Goldstein et al 2013;Kobayashi et al 2012). These observations suggest that histone chaperoning may be a common mechanism to many of NPM1 and NCL's functions;…”

“…Interestingly, the observation that NPM1 is found in a complex with CENP-A, a protein that is substituted for histone H3 in centrosomal nucleosomes, suggests that the histone chaperone activity of NPM1 may be important for its regulation of centrosomal replication (Foltz et al 2009). The collective significance of these numerous functions of NPM1 are underlined by the observation that mouse models of both NPM1 haploinsufficiency (NPM1 +/-) and hypomorphism (NPM1 hm/hm ) are embryonically lethal and exhibit numerous severe neurological and hematological developmental failures prior to termination (Grisendi et al 2005).…”

Formin-mediated epigenetic maintenance of centromere identity

“…7,39 The Mis18 complex is crucial for the recruitment of Holliday junction recognition protein (HJURP), a chaperon that binds to CENP-A in a prenucleosomal complex, to the centromere to execute its nucleosome assembly functions for new CENP-A. 5,6,40 Notably, the localization of HJURP at G1 centromeres appears to be transient, as HeLa cells yield a 2»3 hr time window in early G1 in which HJURP can be detected on the centromere. Knocking down mDia2 does not affect HJURP recruitment onto the centromere.…”

“…We now know that mammalian cells address this issue by replenishing the CENP-A level per centromere in early G1 phase of the cell cycle, right after the previous round of genome division and before the next round of DNA replication. 2 Although several important stages and molecular players have been identified to license, load and stabilize newly synthesized CENP-A proteins at centromeres labeled with preexisted and diluted CENP-A, [3][4][5][6][7] a complete understanding is missing regarding how new CENP-A proteins become stably incorporated into centromeric nucleosomes during early G1.…”