Ground-breaking study reveals dynamics of DNA replication `licensing'
Date:
January 26, 2022
Source:
University of North Carolina Health Care
Summary:
A new study has illuminated an important process that occurs
during cell division and is a likely source of DNA damage under
some circumstances, including cancer.
FULL STORY ==========================================================================
A new study from scientists at the UNC School of Medicine has illuminated
an important process that occurs during cell division and is a likely
source of DNA damage under some circumstances, including cancer.
==========================================================================
The scientists, who reported their findings in Nucleic Acids Research,
devised a sophisticated experimental platform for studying the process
called "origin licensing." Cells use this process to regulate, or
"license" the replication of their genomes during cell division.
The researchers revealed for the first time the dynamics of this
process. They showed in particular how these dynamics differ -- and
bring different risks of DNA damage during replication -- in the two
basic states of genomic DNA, the "euchromatin" state which is relatively
loose and open for gene activity, and the "heterochromatin" state which
is wound more tightly to silence gene activity.
"Our findings may help explain, for example, why certain portions of the
genome are relatively susceptible to DNA damage during replication in
some cancer cells," said study senior author Jean Cook, PhD, professor
of biochemistry and biophysics at the UNC School of Medicine and member
of the UNC Lineberger Comprehensive Cancer Center.
Origin licensing occurs in the initial, preparatory phase of cell
replication, known as the G1 phase. It involves sets of special
enzymes that attach to the DNA in chromosomes at various locations where DNA-copying is to originate. The enzymes essentially license the copying
of DNA so that cells don't copy their genomes more than once.
Cook and other scientists have described in prior studies the basic
process of origin licensing, and have identified proteins that make
it happen. But this study, for the first time, revealed in detail
how the process unfolds over time in cells as they prepare for cell
division. Study first author Liu Mei, PhD, a postdoctoral fellow in
the Cook laboratory, combined still and time-lapse microscopic imaging techniques to accomplish this feat.
========================================================================== "What Liu did was incredibly painstaking and meticulous, a technical
tour de force," Cook said.
As an initial demonstration of her experimental platform, Mei compared
the origin licensing process, with its loading of licensing enzymes, in
the two main states of the genome -- euchromatin and heterochromatin. She
found an important difference.
"Essentially heterochromatin -- more compacted DNA -- loads these
licensing enzymes relatively late compared to what we observe in the
more open euchromatin," Mei said.
This finding hinted, at least, that in dividing cells with an abnormally shortened G1 phase, the more compacted DNA in the cell genome might
never be fully licensed for replication, potentially resulting in
large mutations during replication and even cell death. Confirming this possibility, the researchers found that when they artificially shortened
the G1 phase in test cells, there was significantly more under-replication
and DNA damage in heterochromatin regions of the cells' genomes, compared
to the euchromatin regions.
Cells can have a shortened G1 phase for different reasons, including
due to cancer. Thus the study suggests that the "genomic instability"
or tendency to develop more mutations of some cancer types, as well as
the genomic locations of that instability, might be explained in part
by faulty origin licensing.
The study also establishes the researchers' experimental platform as
a tool for further studies of origin licensing dynamics and genomic instability, studies that might someday yield new strategies against
cancers, for example.
Funding was provided by the National Institutes of Health (R01GM102413, R01GM083024, R35GM141833, R01-GM138834).
========================================================================== Story Source: Materials provided by
University_of_North_Carolina_Health_Care. Note: Content may be edited
for style and length.
========================================================================== Journal Reference:
1. Liu Mei, Katarzyna M Kedziora, Eun-Ah Song, Jeremy E Purvis,
Jeanette
Gowen Cook. The consequences of differential origin licensing
dynamics in distinct chromatin environments. Nucleic Acids Research,
2022; DOI: 10.1093/nar/gkac003 ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2022/01/220126165543.htm
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