Prolyl isomerization of the CENP-A N-terminus regulates centromeric integrity in fission yeast. Issue 3 (29th November 2017)

• Record Type: Journal Article
• Authors: Tan, Hwei Ling; Lim, Kim Kiat; Yang, Qiaoyun; Fan, Jing-Song; Sayed, Ahmed Mahmoud Mohammed; Low, Liy Sim; Ren, Bingbing; Lim, Teck Kwang; Lin, Qingsong; Mok, Yu-Keung; Liou, Yih-Cherng; Chen, Ee Sin
• Is Part Of: Nucleic acids research. Volume 46:Issue 3(2018)
• Page Start: 1167
• Page End: 1179
• Publication Date: 2017-11-29
• Subjects: Nucleic acids -- Periodicals; Molecular biology -- Periodicals; 572.805
• DOI: 10.1093/nar/gkx1180
• Languages: English
• ISSNs: 0305-1048

Abstract

Abstract: Centromeric identity and chromosome segregation are determined by the precise centromeric targeting of CENP-A, the centromere-specific histone H3 variant. The significance of the amino-terminal domain (NTD) of CENP-A in this process remains unclear. Here, we assessed the functional significance of each residue within the NTD of CENP-A from Schizosaccharomyces pombe (SpCENP-A) and identified a proline-rich 'GRANT' (G enomic stability-R egulating site within CENP-A N -T erminus) motif that is important for CENP-A function. Through sequential mutagenesis, we show that GRANT proline residues are essential for coordinating SpCENP-A centromeric targeting. GRANT proline-15 (P15), in particular, undergoes cis – trans isomerization to regulate chromosome segregation fidelity, which appears to be carried out by two FK506-binding protein (FKBP) family prolyl cis–trans isomerases. Using proteomics analysis, we further identified the SpCENP-A-localizing chaperone Sim3 as a SpCENP-A NTD interacting protein that is dependent on GRANT proline residues. Ectopic expression of sim3 + complemented the chromosome segregation defect arising from the loss of these proline residues. Overall, cis–trans proline isomerization is a post-translational modification of the SpCENP-A NTD that confers precise propagation of centromeric integrity in fission yeast, presumably via targeting SpCENP-A to the centromere.