title: Transient endoreplication down-regulates the kinesin-14 HSET and contributes to genomic instability.
abstract: Polyploid cancer cells exhibit chromosomal instability (CIN), which is associated with tumorigenesis and therapy resistance. The mechanisms that induce polyploidy and how these mechanisms contribute to CIN are not fully understood. Here we evaluate CIN in human cells that become polyploid through an experimentally induced endoreplication cycle. When these induced endoreplicating cells (iECs) returned to mitosis, it resulted in aneuploidy in daughter cells. This aneuploidy resulted from multipolar divisions, chromosome missegregation, and failure in cytokinesis. The iECs went through several rounds of division, ultimately spawning proliferative cells of reduced ploidy. iECs have reduced levels of the kinesin-14 HSET, which likely accounts for the multipolar divisions, and overexpression of HSET reduced spindle multipolarity. However, HSET overexpression had only mild effects on CIN, suggesting that additional defects must contribute to genomic instability in dividing iECs. Overall our results suggest that transient endoreplication cycles generate a diverse population of proliferative aneuploid cells that have the potential to contribute to tumor heterogeneity.
authors.affiliation: Department of Biology, Indiana University, Bloomington, IN 47405.
authors.forename: Shengyao
authors.initials: S
authors.lastname: Chen
authors.affiliation: Medical Sciences Program, Indiana University, Bloomington, IN 47405.
authors.forename: Jane R
authors.initials: JR
authors.lastname: Stout
authors.affiliation: Medical Sciences Program, Indiana University, Bloomington, IN 47405.
authors.forename: Sathiya
authors.initials: S
authors.lastname: Dharmaiah
authors.affiliation: Department of Biology, Indiana University, Bloomington, IN 47405.
authors.forename: Sarah
authors.initials: S
authors.lastname: Yde
authors.affiliation: Department of Biology, Indiana University, Bloomington, IN 47405 bcalvi@indiana.edu cwalczak@indiana.edu.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Calvi
authors.affiliation: Medical Sciences Program, Indiana University, Bloomington, IN 47405 bcalvi@indiana.edu cwalczak@indiana.edu.
authors.forename: Claire E
authors.initials: CE
authors.lastname: Walczak
mesh_terms: D000782:Aneuploidy; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018385:Centrosome / Q000378:metabolism / Q000502:physiology; D043171:Chromosomal Instability / Q000235:genetics* / Q000502:physiology; D002875:Chromosomes; D015536:Down-Regulation; D062951:Endoreduplication / Q000235:genetics; D042822:Genomic Instability / Q000235:genetics / Q000502:physiology; D006801:Humans; D016547:Kinesins / Q000235:genetics / Q000378:metabolism*; D008938:Mitosis / Q000235:genetics; D011123:Polyploidy; D008941:Spindle Apparatus / Q000378:metabolism; D064047:Spindle Poles / Q000378:metabolism
chemical_list: C486566:KIFC1 protein, human; D016547:Kinesins