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The Tye/Zhai group is continuing
to view the MCM complex at different
stages of the DNA replication cycle,
combining what is seen through
cryo-EM imaging with genetics and
biochemistry to build atomic models
and continuously add to fundamental
knowledge. Prof Tye is also working
with other HKUST colleagues, including
NMR specialist Prof Guang Zhu, Prof
Xuhui Huang on molecular dynamic
simulations, and with mathematicians
who can help in writing algorithms for
image reconstructions.
Human DNA
and the Origins of Life
“I don’t know about aliens. But here
on Earth, bacteria, archaea, all kinds
of life, as far as we know, involve DNA
replication,” noted Prof Guang Zhu. “It is
one of the most fundamental biological
processes. How can Nature achieve such
outstanding precision time after time in
such a complex process? I want to know
the detailed molecular mechanism
involving human DNA replication, the
malfunctions that can cause cancer
and other diseases, and to work toward
strategies for the potential treatment of
these diseases.”
Prof Zhu’s lab focuses on the
challenging task of creating the human
proteins he studies and the regulation
of cell proliferation and differentiation,
when a cell moves from non-specialized
to a specific type of cell, such as a lung cell
or a liver cell; and the application of new
knowledge to assist drug development.
Breakthroughs in revealing structures
and mechanisms in human DNA
replication proteins include determining
PROF BIK-KWOON YEUNG TYE
Visiting Professor of Life Science
When you can’t see clearly,
you can only speculate.
Now we can finally see
the structure, we know
what information to build on
challenge. Rather than going through
a labor-intensive process of purifying
individual components and assembling
them in a test tube, through finesse and
perseverance he managed to purify pre-
assembled MCM2-7 double hexamers
from within yeast cells in a sufficient
amount and quality for cryo-EM imaging.
Prof Tye’s second discovery was
published in
Nature Structural and
Molecular Biology
in 2017. The team
found that the single hexamer precursor
of the MCM double hexamer in yeast
formed a coiled structure – rather than
the current suggested model of a
closed-ring structure – giving new
insights into double hexamer
formation and indicating a
spring-action mechanism may
be involved in origin melting
and the unwinding of the DNA.
The single hexamer also forms the
core of the helicase that unwinds
DNA by encircling and traveling on one
of the two strands. The fact that the
core of this unwinding machine is a coil/
spring suggests that the driving force
that separates the two strands may be
the repeated action of the spring.
The leading work is drawing
scientific attention globally to the
possibilities that await with the cryo-
EM resolution revolution, as it has been
labeled. “You could see the excitement
when I reported the atomic model for
the MCM complex at a meeting for
the first time,” Prof Tye said. “Clearly,
researchers in the field feel that we can
now move forward. If we can solve one
part, then we can solve more parts, and
by putting them together, we will see the
whole DNA replication machine.”
Prof Bik-Kwoon Yeung Tye (left)
with Dr Yuanliang Zhai.
Prof Tye’s finding suggests a spring-action model for the MCM during the initial origin melting and the subsequent DNA unwinding (shown in figure).
MCM
