Science Advances,
Journal Year:
2024,
Volume and Issue:
10(23)
Published: June 5, 2024
Inheritance
of
epigenetic
information
is
critical
for
maintaining
cell
identity.
The
transfer
parental
histone
H3-H4
tetramers,
the
primary
carrier
modifications
on
proteins,
represents
a
crucial
yet
poorly
understood
step
in
inheritance
information.
Here,
we
show
lagging
strand
DNA
polymerase,
Pol
δ,
interacts
directly
with
and
that
interaction
between
δ
sliding
clamp
PCNA
regulates
to
strands,
most
likely
independent
their
roles
synthesis.
When
combined,
mutations
at
Mcm2
compromise
result
greater
reduction
nucleosome
occupancy
nascent
chromatin
than
either
alone.
Last,
contributes
positioning
chromatin.
On
basis
these
results,
suggest
PCNA–Pol
complex
couples
synthesis
transfer,
facilitating
inheritance.
Annual Review of Genetics,
Journal Year:
2019,
Volume and Issue:
53(1), P. 445 - 482
Published: Oct. 2, 2019
Structural
maintenance
of
chromosomes
(SMC)
complexes
are
key
organizers
chromosome
architecture
in
all
kingdoms
life.
Despite
seemingly
divergent
functions,
such
as
segregation,
maintenance,
sister
chromatid
cohesion,
and
mitotic
compaction,
it
appears
that
these
function
via
highly
conserved
mechanisms
they
represent
a
novel
class
DNA
translocases.
Annual Review of Biochemistry,
Journal Year:
2022,
Volume and Issue:
91(1), P. 107 - 131
Published: March 23, 2022
DNA
replication
in
eukaryotic
cells
initiates
from
large
numbers
of
sites
called
origins.
Initiation
these
origins
must
be
tightly
controlled
to
ensure
the
entire
genome
is
precisely
duplicated
each
cell
cycle.
This
accomplished
through
regulation
first
two
steps
replication:
loading
and
activation
replicative
helicase.
Here
we
describe
what
known
about
mechanism
reactions
a
genetic,
biochemical,
structural
perspective,
focusing
on
recent
progress
using
proteins
budding
yeast.
Molecular Cell,
Journal Year:
2020,
Volume and Issue:
78(5), P. 926 - 940.e13
Published: May 4, 2020
The
eukaryotic
replisome,
organized
around
the
Cdc45-MCM-GINS
(CMG)
helicase,
orchestrates
chromosome
replication.
Multiple
factors
associate
directly
with
CMG,
including
Ctf4
and
heterotrimeric
fork
protection
complex
(Csm3/Tof1
Mrc1),
which
has
important
roles
aiding
normal
replication
rates
stabilizing
stalled
forks.
How
these
proteins
interface
CMG
to
execute
functions
is
poorly
understood.
Here
we
present
3
3.5
Å
resolution
electron
cryomicroscopy
(cryo-EM)
structures
comprising
Ctf4,
at
a
fork.
provide
high-resolution
views
of
CMG-DNA
interactions,
revealing
mechanism
for
strand
separation,
show
Csm3/Tof1
"grip"
duplex
DNA
ahead
via
network
interactions
efficient
pausing.
Although
Mrc1
was
not
resolved
in
our
structures,
determine
its
topology
replisome
by
cross-linking
mass
spectrometry.
Collectively,
work
reveals
how
four
highly
conserved
components
collaborate
facilitate
progression
maintain
genome
stability.
Cell,
Journal Year:
2023,
Volume and Issue:
186(5), P. 1050 - 1065.e19
Published: Feb. 6, 2023
Chromatin
landscapes
are
disrupted
during
DNA
replication
and
must
be
restored
faithfully
to
maintain
genome
regulation
cell
identity.
The
histone
H3-H4
modification
landscape
is
by
parental
recycling
of
new
histones.
How
impacts
on
H2A-H2B
currently
unknown.
Here,
we
measure
modifications
H2A.Z
across
the
cycle
using
quantitative
genomics.
We
show
that
H2AK119ub1,
H2BK120ub1,
recycled
accurately
replication.
Modified
segregated
symmetrically
daughter
strands
via
POLA1
lagging
strand,
but
independent
recycling.
Post-replication,
variant
quickly
restored,
H2AK119ub1
guides
accurate
restoration
H3K27me3.
This
work
reveals
epigenetic
transmission
identifies
cross
talk
between
in
epigenome
propagation.
propose
rapid
short-term
memory
facilitates
stable
chromatin
states.
Nature Genetics,
Journal Year:
2023,
Volume and Issue:
55(9), P. 1567 - 1578
Published: Sept. 1, 2023
Modified
parental
histones
are
segregated
symmetrically
to
daughter
DNA
strands
during
replication
and
can
be
inherited
through
mitosis.
How
this
may
sustain
the
epigenome
cell
identity
remains
unknown.
Here
we
show
that
transmission
of
histone-based
information
maintains
fidelity
embryonic
stem
plasticity.
Asymmetric
segregation
H3-H4
in
MCM2-2A
mutants
compromised
mitotic
inheritance
histone
modifications
globally
altered
epigenome.
This
included
widespread
spurious
deposition
repressive
modifications,
suggesting
elevated
epigenetic
noise.
Moreover,
H3K9me3
loss
at
repeats
caused
derepression
H3K27me3
redistribution
across
bivalent
promoters
correlated
with
misexpression
developmental
genes.
mutation
challenged
dynamic
transitions
cellular
states
cycle,
enhancing
naïve
pluripotency
reducing
lineage
priming
G1.
Furthermore,
competence
was
diminished,
correlating
impaired
exit
from
pluripotency.
Collectively,
argues
a
correctly
balanced
chromatin
landscape
able
support
mammalian
differentiation.
Molecular Cell,
Journal Year:
2023,
Volume and Issue:
83(16), P. 2911 - 2924.e16
Published: July 27, 2023
During
eukaryotic
DNA
replication,
Pol
α-primase
generates
primers
at
replication
origins
to
start
leading-strand
synthesis
and
every
few
hundred
nucleotides
during
discontinuous
lagging-strand
replication.
How
is
targeted
forks
prime
not
fully
understood.
Here,
by
determining
cryoelectron
microscopy
(cryo-EM)
structures
of
budding
yeast
human
replisomes
containing
α-primase,
we
reveal
a
conserved
mechanism
for
the
coordination
priming
replisome.
binds
directly
leading
edge
CMG
(CDC45-MCM-GINS)
replicative
helicase
via
complex
interaction
network.
The
non-catalytic
PRIM2/Pri2
subunit
forms
two
interfaces
with
that
are
critical
in
vitro
cell
growth.
These
interactions
position
primase
catalytic
PRIM1/Pri1
above
exit
channel
template
single-stranded
(ssDNA),
revealing
why
occurs
efficiently
only
on
elucidating
overcome
competition
from
RPA
initiate
primer
synthesis.
Cell,
Journal Year:
2024,
Volume and Issue:
187(18), P. 5029 - 5047.e21
Published: Aug. 1, 2024
The
inheritance
of
parental
histones
across
the
replication
fork
is
thought
to
mediate
epigenetic
memory.
Here,
we
reveal
that
fission
yeast
Mrc1
(CLASPIN
in
humans)
binds
H3-H4
tetramers
and
operates
as
a
central
coordinator
symmetric
histone
inheritance.
mutants
key
connector
domain
disrupted
segregation
lagging
strand
comparable
Mcm2
histone-binding
mutants.
Both
showed
clonal
asymmetric
loss
H3K9me-mediated
gene
silencing.
AlphaFold
predicted
co-chaperoning
by
Mcm2,
with
bridging
binding.
Biochemical
functional
analysis
validated
this
model
revealed
duality
function:
disabling
binding
lagging-strand
recycling
while
another
mutation
impaired
leading
recycling.
We
propose
toggles
between
pathways,
part
intra-replisome
co-chaperoning,
ensure
transmission
both
daughter
cells.