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Misorientation and reduced stretching
of aligned sister kinetochores promote chromosome missegregation in
EB1- or APC-depleted cells
V M Draviam1,
I Shapiro1, B Aldridge2
and P K Sorger1, 2
1 Department of
Biology, Massachusetts Institute of Technology, Cambridge, MA, USA. 2 Biological
Engineering Division, Massachusetts Institute of Technology,
Cambridge, MA, USA.
To whom correspondence should be addressed: P K Sorger, Department
of Biology, 68-371 MIT, 77 Mass Avenue, Massachusetts Institute of
Technology, Cambridge, MA 02139, USA. Tel.: +1 617 252 1806/1648; Fax:
+1 617 253 8550; E-mail: psorger@mit.edu
Received 21 September 2005; Accepted 4 May 2006; Published online 8
June 2006.
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The correct formation of stable but
dynamic links between chromosomes and spindle microtubules (MTs) is
essential for accurate chromosome segregation.
However, the molecular
mechanisms by which kinetochores bind MTs and checkpoints monitor this
binding remain poorly understood.
In this paper, we analyze the
functions of six kinetochore-bound MT-associated proteins (kMAPs)
using RNAi, live-cell microscopy and quantitative image
analysis.
We find that RNAi-mediated
depletion of two kMAPs, the adenomatous polyposis coli protein (APC)
and its binding partner, EB1, are unusual in affecting the movement
and orientation of paired sister chromatids at the metaphase plate
without perturbing kinetochore–MT attachment per se.
Quantitative analysis shows
that misorientation phenotypes in metaphase are uniform across
chromatid pairs even though chromosomal loss (CIN) during anaphase is
sporadic.
However, errors in kinetochore
function generated by APC or EB1 depletion are detected poorly if at
all by the spindle checkpoint, even though they cause chromosome
missegregation.
We propose that impaired EB1 or
APC function generates lesions invisible to the spindle checkpoint and
thereby promotes low levels of CIN expected to fuel aneuploidy and
possibly tumorigenesis.
Keywords:
aneuploidy, chromosome segregation, kinetochore,
microtubule-associated protein
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