Seckel He la cells and blocked mitotic spindle

Seckel syndrome, an autosomal recessive disorder is characterized
by growth and mental retardation, microcephaly, distinct facial features like
big eyes, beak-like nose, narrow face, and receding lower jaw. The mutation in ataxia
telangiectasia and Rad3 related protein (ATR) gene located on chromosome
3q22.1-q24 result in Seckel syndrome.  There
are 8 different subtypes of SS based on specific gene alteration.
CDK5RAP2 gene expression product is a centrosomal protein that is
essential for spindle formation and is also responsible for autosomal recessive
primary microcephaly. Mutation in CDK5RAP2 results in erroneous mitosis and defective
spindle assembly, resulting in cells with abnormal nuclei and centrosomal
pattern. These observations highlight the importance of centrosomal and mitotic
proteins in the pathogenesis of the disease. (Yigit et al. 2015) Mutations in
the gene encoding pericentrin (PCNT) leads to its loss from the
centrosome.  The pericentrin is required
for anchoring structural and regulatory proteins also cause Seckel syndrome. Also,
cells originating from PCNT (PCNT-Seckel) Seckel syndrome patients have defective
checkpoint signaling that is dependent on ATR function, indicate a link between
centrosomal structural protein with DNA damage signaling. (Griffith et al.
2008). These findings also indicate that other microcephaly genes involved in
either DDR or centrosomal function may be involved in developmental
pathways that regulate human body and brain size.



MBC (methyl 2-benzimidazolecarbam) – MT poison

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        Carbendazim is a
broad-spectrum benzimidazole antifungal with potential antimitotic and
antineoplastic activities.

        MBC impacts mitosis
and cell division, by inhibiting the polymerization of tubulin to form
microtubules and suppressing their dynamic instability. It induces a
conformational change in the tubulin itself hindering modification of its
cysteine residues. The cysteine residues are vital for assembly of tubulin
monomers into microtubule. MBC inhibits proliferation of cells and arrests
mitosis by preventing microtubule dynamics at 8?M concentration. It induces
mitotic spindle anomalies and lessens the metaphase inter centromere space of
sister chromatids, indicating a decrease of tension at kinetochores, initiating
cell cycle checkpoints and leading to metaphase arrest and ultimately

         Microtubule dynamics are carefully regulated
during the cell division cycle by various cellular regulators. Many antitumor
drugs and natural compounds also alter the polymerization dynamics of MTs,
arresting mitosis, and consequently, inducing cell death by apoptosis. Some of
these drugs inhibit microtubule polymerization at high drug concentrations
while some compounds stimulate MT polymerization and stabilize microtubules at
high concentrations. Interestingly, at lower levels, all drugs have a common mechanism
of action; they suppress the MT dynamics without considerably altering the mass
of microtubules in the cell. The drugs bind to diverse sites on tubulin and MT,
and they also have varied effects on microtubule dynamics. However, they all
block mitosis at the transition of metaphase/anaphase and induce apoptosis.
(Jordan MA, 2008). Benomyl (MBC) inhibits the polymerization of brain tubulin
into microtubules and actively suppresses the dynamic instability of brain
microtubules without affecting the catastrophe or rescue frequencies. In the
studies, it also inhibited proliferation of the He la cells and blocked mitotic
spindle function by disturbing microtubule and chromosome organization. The
effects of benomyl on microtubules and mitosis along with its relatively low
toxicity indicate that it might be incorporated as an adjuvant in cancer
chemotherapy (Gupta et al. 2004). MBC also disturbed microtubule-kinetochore
attachment and chromosome alignment at the metaphase plate. Treatment with benomyl
also results in a decrease in tension at kinetochores by significantly reducing
the distance between the sister kinetochore pairs. Benomyl also decreases the
inter centrosomal distance in mitotic He La cells and blocks the cells at
mitosis. (Rathinasamy et al. 2006). New genes namely, CIN1, CIN2, and CIN4,
influencing microtubule function in Saccharomyces cerevisiae have been identified
by screening for mutants that display sensitivity to the anti-microtubule drug
benomyl. Further studies with cin mutants suggest that these three genes act
together in the common pathway or structure that influence microtubule
function. (Stearns et al. 1990). Drugs like carbendazim, thiabendazole, and
chloropropham at various concentrations completely arrest cell division along with
distinct morphological variations. The cells either became enlarged or they are
small and rounded on treatment with carbendazim, and chloropropham respectively.
Further experiments also showed that each drug have different transition
points; for example, amiprophos methyl affected a very early stage while carbendazim
and thiabendazole block cell division cycle at later stage, indicating that
these drugs affect cell cycle in fission yeast either by inhibiting tubulin
synthesis (early stage as with amiprophos methyl) or by hindering microtubule
assembly (as with carbendazim and thiabendazole). These drugs are useful in
studies of microtubule synthesis and their role during the cell division cycle
in yeast.  (Walker GM, 1982)