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The Fork and The Kinase A DNA Replication Tale From A CHK1 Perspective 2015 Mutation Research Reviews in Mutation Research
The Fork and The Kinase A DNA Replication Tale From A CHK1 Perspective 2015 Mutation Research Reviews in Mutation Research
Review
The fork and the kinase: A DNA replication tale from a CHK1
perspective
Marina A. Gonzalez Besteiro, Vanesa Gottifredi *
Cell Cycle and Genomic Stability Laboratory, Fundacion Instituto Leloir, CONICET, Buenos Aires, Argentina
A R T I C L E I N F O
A B S T R A C T
Article history:
Received 16 August 2014
Received in revised form 7 October 2014
Accepted 10 October 2014
Available online 22 October 2014
Replication fork progression is being continuously hampered by exogenously introduced and naturally
occurring DNA lesions and other physical obstacles. Checkpoint kinase 1 (Chk1) is activated at
replication forks that encounter damaged DNA. Subsequently, Chk1 inhibits the initiation of new
replication factories and stimulates the ring of dormant origins (those in the vicinity of stalled forks).
Chk1 also avoids fork collapse into DSBs (double strand breaks) and promotes fork elongation. At the
molecular level, the current model considers stalled forks as the site of Chk1 activation and the
nucleoplasm as the location where Chk1 phosphorylates target proteins. This model certainly serves to
explain how Chk1 modulates origin ring, but how Chk1 controls the fate of stalled forks is less clear.
Interestingly, recent reports demonstrating that Chk1 phosphorylates chromatin-bound proteins and
even holds kinase-independent functions might shed light on how Chk1 contributes to the elongation of
damaged DNA. Indeed, such ndings have unveiled a puzzling connection between Chk1 and DNA lesion
bypass, which might be central to promoting fork elongation and checkpoint attenuation. In summary,
Chk1 is a multifaceted and versatile signaling factor that acts at ongoing forks and replication origins to
determine the extent and quality of the cellular response to replication stress.
2014 Elsevier B.V. All rights reserved.
Keywords:
Checkpoint kinase 1 (Chk1)
DNA replication
Translesion synthesis (TLS)
DNA damage
Contents
1.
2.
3.
4.
Checkpoint signals during the S phase and the maintenance of genomic stability . . . . . .
DNA structures and protein networks upstream of Chk1 activation . . . . . . . . . . . . . . . . . .
2.1.
ATRATRIP activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
RPAssDNA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.1.
TopBP1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.2.
Rad17/911 complex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.3.
Pol k . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.4.
2.2.
ATR-mediated Chk1 phosphorylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Claspin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.1.
2.2.2.
PARP1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Chk1 activation and function are tightly linked to its subcellular localization. . . . . . . . . .
3.1.
Chk1 activation takes place in the nucleus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Signals that regulate Chk1 shuttling between chromatin and nucleoplasm . . . . . .
3.2.
Targets of Chk1 in the nucleoplasm and on chromatin . . . . . . . . . . . . . . . . . . . . . .
3.3.
Chk1 function during DNA replication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
The control of origin ring by Chk1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1.
Molecular mechanisms involved in Chk1-dependent control of replication origins
4.2.
Cdk2-dependent control of Cdc45 loading . . . . . . . . . . . . . . . . . . . . . . . . .
4.2.1.
Cdc7-regulated loading of Cdc45 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2.2.
* Corresponding author at: Av. Patricias Argentinas 435, Buenos Aires, Argentina. Tel.: +54 11 5238 7500.
E-mail address: vgottifredi@leloir.org.ar (V. Gottifredi).
http://dx.doi.org/10.1016/j.mrrev.2014.10.003
1383-5742/ 2014 Elsevier B.V. All rights reserved.
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4.2.3.
TopBP1/Treslin interaction and the control of Cdc45 loading .
The control of replication fork stability by Chk1. . . . . . . . . . . . . . . . . . .
The checkpoint regulates replisome stability . . . . . . . . . . . . . .
4.3.1.
Chk1 promotes TLS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.3.2.
Chk1-mediated control of DSB formation and repair. . . . . . . .
4.3.3.
Chk1 contribution to cell survival . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.4.
Attenuation of Chk1 signals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Active Chk1 is preferentially degraded . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1.
5.2.
Chk1 dephosphorylation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Checkpoint recovery beyond Chk1 inactivation . . . . . . . . . . . . . . . . . . .
5.3.
Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.3.
5.
6.
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Fig. 1. Chk1 activation models over one decade. Year 2000: The uncoupling of the
helicase and the replicative polymerase Pol e generates long stretches of RPA
ssDNA, a pre-requisite to recruit and activate ATR. ATR then phosphorylates Chk1,
resulting in Chk1 activation. Note that in this model only the leading strand is able
to initiate checkpoint signaling. Year 2005: ATR activation is preceded by the
loading of the 9-1-1 clamp onto the 50 junction of an Okazaki fragment elongated by
Pol d. Note that in this model only the lagging strand is able to initiate checkpoint
signaling. Year 2013: Current model for checkpoint activation (for simplication
not all checkpoint components are shown). The TLS polymerase Pol k elongates
primers at the leading strand. Therefore, both strands contain primertemplate
junctions and thus equally allow the loading of the 9-1-1 clamp. Therefore, ATRdependent Chk1 activation originates from the leading and lagging strands.
170
171
Fig. 2. Proper Chk1 activation and function require a dynamic, tightly regulated balance of its subcellular localization. A fork initiating checkpoint signaling is shown (for
simplication one of the parental strands is not shown). Under unperturbed conditions, a fraction of Chk1 is recruited to chromatin, in part through its C-terminal PIP motif
that binds PCNA. ATR then phosphorylates Chk1 on serines 317 and 345, and ATR-activated Chk1 engages in auto-phosphorylation of serine 296 (represented as the third P in
the soluble Chk1). Upon genotoxic stress, at least two mechanisms contribute to Chk1 accumulation at sites of DNA damage: (a) cytoplasmic, p90 RSK-dependent
phosphorylation of S280 serves to accumulate Chk1 in the nucleus (whether this modication is lost or kept upon nuclear entry is not known); (b) the N-terminal PbR motif in
Chk1 binds PAR chains synthetized by and attached to PARP1. As a result of these two mechanisms and of increased loading of ATR onto stalled forks (Fig. 1), more Chk1
molecules get activated under perturbed in comparison to unperturbed conditions. Physiologically active and stress-activated Chk1 phosphorylate proteins both at
chromatin and in the nucleoplasm (see text for details).
172
Fig. 3. Chk1 functions in DNA replication. A nucleus in S phase with replication factories foci is shown. The arrow represents the incidence of DNA damage upon a given
factory. Note that in unperturbed conditions endogenous damage can account for Chk1 activation. Active Chk1 performs its function at the same replication fork that activates
it (in cis) or, after being released to the nucleoplasm, at other replication factories (in trans). In trans, Chk1 inhibits origin ring by preventing Cdc45 loading. In unperturbed
conditions this is achieved by Chk1-dependent Cdc25A degradation. Upon genotoxic stress, apart from impinging on Cdk2 activity, Chk1 might also inactivate Cdc7 and
disrupt the interaction between TopBP1 and treslin; both mechanisms lead to impaired loading of the Cdc45-MCM2-7-GINS replicative helicase. In cis, Chk1 prevents DSB
formation by unknown mechanisms, thereby stabilizing forks. Chk1 also aids HR repair of collapsed forks by positively regulating the recruitment of Rad51 and limits
genomic instability by restraining the activity of Mus81 and other nucleases. In addition, Chk1 might promote the elongation of forks that have stalled and allow dormant
origin ring to ensure that DNA replication is completed (not represented).
173
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175
176
Fig. 4. Reversible checkpoint activation requires TLS. (A) Isolated model for
checkpoint activation: DNA lesions accumulate randomly in the DNA. A fork that
encounters a lesion triggers ATR and Chk1 activation (1). Active Chk1 dissociates
from chromatin, inhibiting origin ring and creating a time window for DNA repair
(2). DNA repair removes DNA lesions (40 ). Chk1 signal is attenuated in the
nucleoplasm by multiple mechanisms, including degradation of active Chk1. As a
consequence, DNA replication is resumed at inhibited origins (40 ) but not at forks in
check (50 ). (B) A checkpoint and TLS coordination model: when Chk1 is released to
control origin ring, it promotes the loading and activation of Pol h at the fork in
check (3). As in (A), origins are no longer inhibited after active Chk1 is degraded. In
contrast to (A), Chk1 activation and its release from chromatin enable a TLSdependent restoration of DNA elongation at forks in check (4). DNA replication at
stalled forks is thus resumed after efcient lesion removal, thereby avoiding fork
collapse (5).
177
178
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