DDA3 recruits microtubule depolymerase Kif2a to spindle poles and controls spindle dynamics and mitotic chromosome movement.
Dynamic turnover of the spindle is a driving force for chromosome congression and segregation in mitosis. Through a functional genomic analysis, we identify DDA3 as a previously unknown regulator of spindle dynamics that is essential for mitotic progression. DDA3 depletion results in a high frequency of unaligned chromosomes, a substantial reduction in tension across sister kinetochores at metaphase, and a decrease in the velocity of chromosome segregation at anaphase. DDA3 associates with the mitotic spindle and controls microtubule (MT) dynamics. Mechanistically, DDA3 interacts with the MT depolymerase Kif2a in an MT-dependent manner and recruits Kif2a to the mitotic spindle and spindle poles. Depletion of DDA3 increases the steady-state levels of spindle MTs by reducing the turnover rate of the mitotic spindle and by increasing the rate of MT polymerization, which phenocopies the effects of partial knockdown of Kif2a. Thus, DDA3 represents a new class of MT-destabilizing protein that controls spindle dynamics and mitotic progression by regulating MT depolymerases.
Jang
Chang-Young
CY
Department of Biological Sciences, Stanford University, Stanford, CA 94305, USA.
Wong
Jim
J
Coppinger
Judith A
JA
Seki
Akiko
A
Yates
John R
JR
Fang
Guowei
G
D002460:Cell Line; D002853:Chromatography, Liquid; D003001:Cloning, Molecular; D006367:HeLa Cells; D006801:Humans; D007668:Kidney; D016547:Kinesins / Q000378:metabolism*; D018386:Kinetochores / Q000502:physiology / Q000648:ultrastructure; D013058:Mass Spectrometry; D008938:Mitosis / Q000502:physiology*; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins / Q000378:metabolism; D008941:Spindle Apparatus / Q000201:enzymology / Q000502:physiology*; D014162:Transfection
C509805:KIF2A protein, human; C485740:PSRC1 protein, human; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D016547:Kinesins