Cohesin
is
a
trimeric
complex
containing
pair
of
SMC
proteins
(Smc1
and
Smc3)
whose
ATPase
domains
at
the
end
long
coiled
coils
(CC)
are
interconnected
by
Scc1.
During
interphase,
it
organizes
chromosomal
DNA
topology
extruding
loops
in
manner
dependent
on
Scc1’s
association
with
two
large
hook
shaped
called
SA
(yeast:
Scc3)
Nipbl
(Scc2).
The
latter’s
replacement
Pds5
recruits
Wapl,
which
induces
release
from
chromatin
via
process
requiring
dissociation
N-terminal
domain
(NTD)
Smc3.
If
blocked
Esco
(Eco)-mediated
Smc3
acetylation,
cohesin
merely
maintains
pre-existing
loops,
but
third
fate
occurs
during
replication,
when
Pds5-containing
associates
Sororin
forms
structures
that
hold
sister
DNAs
together.
How
Wapl
blocks
has
hitherto
remained
mysterious.
In
twenty
years
since
their
discovery,
not
single
testable
hypothesis
been
proposed
as
to
role.
Here,
AlphaFold
2
(AF)
three-dimensional
protein
structure
predictions
lead
us
propose
formation
quarternary
between
SA,
Pds5,
NTD,
latter
juxtaposed
(and
subsequently
sequestered
by)
highly
conserved
cleft
within
Wapl’s
C-terminal
(CTD).
AF
also
reveals
how
arises
distortion
Smc3’s
CC
induced
engagement
domains,
acetyl
transferases
recruited
prevents
binding
Smc3/Scc1
interface.
Our
hypotheses
explain
phenotypes
numerous
existing
mutations
testable.
Trends in Cell Biology,
Год журнала:
2023,
Номер
33(10), С. 860 - 871
Опубликована: Апрель 15, 2023
Cohesin
folds
the
genome
in
dynamic
chromatin
loops
and
holds
sister
chromatids
together.
NIPBLScc2
is
currently
considered
cohesin
loader,
a
role
that
may
need
reevaluation.
NIPBL
activates
ATPase,
which
required
for
topological
entrapment
of
DNAs
to
fuel
DNA
loop
extrusion,
but
not
association.
Mechanistic
dissection
these
processes
suggests
both
STAG
subunit
bind
DNA.
also
regulates
conformational
switches
complex.
Interactions
with
factors,
including
remodelers,
replication
proteins,
transcriptional
machinery,
affect
loading
distribution.
Here,
we
discuss
recent
research
addressing
how
modulates
activities
its
mutation
causes
developmental
disorder,
Cornelia
de
Lange
Syndrome
(CdLS).
Proceedings of the National Academy of Sciences,
Год журнала:
2024,
Номер
121(18)
Опубликована: Апрель 26, 2024
The
DNA
sliding
clamp
PCNA
is
a
multipurpose
platform
for
polymerases
and
many
other
proteins
involved
in
metabolism.
topologically
closed
ring
needs
to
be
cracked
open
loaded
onto
by
loader,
e.g.,
the
well-studied
pentameric
ATPase
complex
RFC
(RFC1-5).
CTF18-RFC
an
alternative
loader
found
recently
bind
leading
strand
polymerase
ε
load
DNA,
but
its
structure
loading
mechanism
have
been
unknown.
By
cryo-EM
analysis
of
vitro
assembled
human
CTF18-RFC–DNA–PCNA
complex,
we
captured
seven
intermediates,
revealing
detailed
3′-ss/dsDNA
junction
CTF18-RFC.
Interestingly,
has
evolved
highly
mobile
CTF18
AAA+
module
likely
lower
activity,
perhaps
avoid
competition
with
limit
role
loading.
To
compensate
lost
stability
due
module,
unique
β-hairpin
motif
that
reaches
across
RFC2
interact
RFC5,
thereby
stabilizing
complex.
Further,
also
contains
separation
pin
locally
melt
from
3′-end
primer;
this
ensures
ability
any
junction,
facilitated
binding
energy
E-plug
major
groove.
Our
study
reveals
structural
features
contributes
broader
understanding
loaders.
Molecular Cell,
Год журнала:
2025,
Номер
85(6), С. 1058 - 1071
Опубликована: Март 1, 2025
The
ring-shaped
cohesin
complex
topologically
entraps
two
DNAs
to
establish
sister
chromatid
cohesion.
Cohesin
also
shapes
the
interphase
chromatin
landscape
by
forming
DNA
loops,
which
it
is
thought
achieve
using
an
in
vitro-observed
loop
extrusion
mechanism.
However,
recent
studies
revealed
that
loop-extrusion-deficient
retains
its
ability
form
suggesting
a
divergence
of
vitro
and
vivo
formation.
Instead
extrusion,
we
examine
whether
forms
loops
mechanism
akin
cohesion
establishment:
sequential
topological
capture
DNAs.
We
explore
similarities
differences
between
"loop
capture"
extrusion"
model,
how
they
compare
at
explaining
experimental
observations,
future
approaches
can
delineate
their
possible
respective
contributions.
extend
our
DNA-DNA
model
for
function
related
structural
maintenance
chromosomes
(SMC)
family
members,
condensin,
Smc5-Smc6
complex,
bacterial
SMC
complexes.
Nature Communications,
Год журнала:
2024,
Номер
15(1)
Опубликована: Июль 3, 2024
The
CRL4-DCAF15
E3
ubiquitin
ligase
complex
is
targeted
by
the
aryl-sulfonamide
molecular
glues,
leading
to
neo-substrate
recruitment,
ubiquitination,
and
proteasomal
degradation.
However,
physiological
function
of
DCAF15
remains
unknown.
Using
a
domain-focused
genetic
screening
approach,
we
reveal
as
an
acute
myeloid
leukemia
(AML)-biased
dependency.
Loss
results
in
suppression
AML
through
compromised
replication
fork
integrity
consequent
accumulation
DNA
damage.
Accordingly,
loss
sensitizes
stress-inducing
therapeutics.
Mechanistically,
discover
that
directly
interacts
with
SMC1A
protein
cohesin
destabilizes
regulatory
factors
PDS5A
CDCA5.
CDCA5
removal
precludes
acetylation
on
chromatin,
resulting
uncontrolled
chromatin
loop
extrusion,
defective
replication,
apoptosis.
Collectively,
our
findings
uncover
endogenous,
cell
autonomous
sustaining
proliferation
post-translational
control
dynamics.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2025,
Номер
unknown
Опубликована: Фев. 23, 2025
Abstract
Structural
maintenance
of
chromosomes
(SMC)
complexes
organize
genomes
by
extruding
DNA
loops,
while
replisomes
duplicate
entire
chromosomes.
These
essential
molecular
machines
must
collide
frequently
in
every
cell
cycle,
yet
how
such
collisions
are
resolved
vivo
remains
poorly
understood.
Taking
advantage
the
ability
to
load
SMC
at
defined
sites
Bacillus
subtilis
genome,
we
engineered
head-on
and
head-to-tail
between
replisome.
Replisome
progression
was
monitored
marker
frequency
analysis,
translocation
time-resolved
ChIP-seq
Hi-C.
We
found
that
do
not
impede
replisome
progression.
By
contrast,
restrict
regardless
collision
orientations.
Combining
experimental
data
with
simulations,
determined
blocked
then
released
from
chromosome.
Occasionally,
can
bypass
continue
translocating.
Our
findings
establish
is
a
barrier
SMC-mediated
DNA-loop
extrusion
,
implications
for
processes
as
chromosome
segregation,
repair,
gene
regulation
require
dynamic
organization
all
organisms.
