HARPing on about the DNA damage response during replication: Figure 1.

Driscoll, Robert; Cimprich, Karlene A.

doi:10.1101/gad.1860609

Cited by 34 publications

(26 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Apparently S-phase checkpoint signaling not only functions as a damage surveillance system but also protects stalled replication forks from collapse by restraining replication origin firing. Besides the role in S-phase checkpoint activation, RPA-ssDNA complex recruits DNA repair proteins such as SMARCAL1 to stalled forks and facilitates the restart of replication forks [26][27][28]. The specific interaction of SMARCAL1 N-terminus with RPA32C is sufficient to localize SMARCAL1 to stalled replication forks to prevent stalled fork collapse by minimizing the accumulation of ssDNA.…”

Section: Discussionmentioning

confidence: 99%

Structure of RPA32 bound to the N‐terminus of SMARCAL1 redefines the binding interface between RPA32 and its interacting proteins

Xie

Jakoncic

et al. 2014

The FEBS Journal

View full text Add to dashboard Cite

, Tipin, UNG2 and XPA. We have solved the high-resolution crystal structure of RPA32 C-terminal domain (RPA32C) in complex with a 26-amino-acid peptide derived from the N-terminus of SMARCAL1 (SMARCAL1N). The RPA32C-SMARCAL1N structure reveals a 1 : 1 binding stoichiometry and displays a well-ordered binding interface. SMARCAL1N adopts a long a-helical conformation with the highly conserved 11 residues aligned on one face of the a-helix showing extensive interactions with the RPA32C domain. Extensive mutagenesis experiments were performed to corroborate the interactions observed in crystal structure. Moreover, the a1/a2 loop of the RPA32C domain undergoes a conformational rearrangement upon SMARCAL1N binding. NMR study has further confirmed that the RPA32C-SMARCAL1N interaction induces conformational changes in RPA32C. Isothermal titration calorimetry studies have also demonstrated that the conserved a-helical motif defined in the current study is required for sufficient binding of RPA32C. Taken together, our study has provided convincing structural information that redefines the common recognition pattern shared by RPA32C interacting proteins. DatabaseThe atomic coordinates of RPA32C in complex with 26-aa SMARCAL1 (SMARCAL1N) peptide have been deposited at the Protein Data Bank with accession code 4MQV. Structured digital abstractRPA32 and SMARCAL1 bind by isothermal titration calorimetry (1,2,3,4,5,6,7,8,9) RPA32 and SMARCAL1 bind by molecular sieving (View interaction) RPA32 and SMARCAL1 bind by x-ray crystallography (View interaction) Tipin and RPA32 bind by isothermal titration calorimetry (1, 2) RPA32 and UNG2 bind by isothermal titration calorimetry (1, 2, 3) SMARCAL1 and RPA32 bind by nuclear magnetic resonance (View interaction) UNG2 and RPA32 bind by nuclear magnetic resonance (View interaction) Tipin and RPA32 bind by nuclear magnetic resonance (View interaction)Abbreviations ITC, isothermal titration calorimetry; NER, nucleotide excision repair; RPA, replication protein A; RPA32C, RPA32 C-terminal domain; SIOD, Schimke immuno-osseous dysplasia; Tipin, Timeless-interacting protein; UNG2, uracil-DNA glycosylase; XPA, xeroderma pigmentosum complementation group A.

show abstract

Section: Discussionmentioning

confidence: 99%

Structure of RPA32 bound to the N‐terminus of SMARCAL1 redefines the binding interface between RPA32 and its interacting proteins

Xie

Jakoncic

et al. 2014

The FEBS Journal

View full text Add to dashboard Cite

show abstract

“…Previous studies by our group and others defined SMARCAL1 as a replication stress response protein that acts to preserve genome integrity during DNA replication Ciccia et al 2009;Driscoll and Cimprich 2009;Postow et al 2009;Yusufzai et al 2009). Immunofluorescent imaging demonstrated that SMARCAL1 accumulates at damaged replication forks due to its interaction with RPA.…”

Section: Discussionmentioning

confidence: 99%

SMARCAL1 catalyzes fork regression and Holliday junction migration to maintain genome stability during DNA replication

Bétous¹,

Mason²,

Rambo³

et al. 2012

Genes Dev.

252

307

View full text Add to dashboard Cite

SMARCAL1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A-like1) maintains genome integrity during DNA replication. Here we investigated its mechanism of action. We found that SMARCAL1 travels with elongating replication forks, and its absence leads to MUS81-dependent double-strand break formation. Binding to specific nucleic acid substrates activates SMARCAL1 activity in a reaction that requires its HARP2 (Hep-A-related protein 2) domain. Homology modeling indicates that the HARP domain is similar in structure to the DNA-binding domain of the PUR proteins. Limited proteolysis, small-angle X-ray scattering, and functional assays indicate that the core enzymatic unit consists of the HARP2 and ATPase domains that fold into a stable structure. Surprisingly, SMARCAL1 is capable of binding three-way and four-way Holliday junctions and model replication forks that lack a designed ssDNA region. Furthermore, SMARCAL1 remodels these DNA substrates by promoting branch migration and fork regression. SMARCAL1 mutations that cause Schimke immunoosseous dysplasia or that inactivate the HARP2 domain abrogate these activities. These results suggest that SMARCAL1 continuously surveys replication forks for damage. If damage is present, it remodels the fork to promote repair and restart. Failures in the process lead to activation of an alternative repair mechanism that depends on MUS81-catalyzed cleavage of the damaged fork.

show abstract

“…This finding provided unique biochemical evidence for the capability of HLTF and Rad5 to facilitate error-free damage bypass by switching the template from the damaged leading strand to the newly synthesized undamaged nascent strand of the lagging arm. In addition to Rad5 and HLTF, the number of enzymes with proven fork reversal activity is continuously growing (31,33,34,42,43), which raises the possibility that many parallel pathways might exist for fork reversal and template switching. However, it has not been examined what happens to the huge protein complex present at the stalled replication fork, collectively referred to as replication machinery.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to HLTF, a fork reversal activity has been indicated for a number of other repair proteins such as the Bloom helicase (BLM), HepA-related protein (HARP), and Fanconi anemia complementation group M (FANCM) (31)(32)(33)(34), which suggests that multiple pathways might exist for template switch-dependent error-free DNA damage bypass. However, all previous fork reversal assays were carried out on naked replication fork-like structures, whereas in vivo a stalled replication fork contains several ssDNA-and dsDNA-bound proteins such as the polymerases, RPA, replication factor C (RFC), and PCNA, which can interfere with DNA remodeling.…”

mentioning

confidence: 99%

Coordinated protein and DNA remodeling by human HLTF on stalled replication fork

Achar

Balogh

Haracska

2011

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Human helicase-like transcription factor (HLTF) exhibits ubiquitin ligase activity for proliferating cell nuclear antigen (PCNA) polyubiquitylation as well as double-stranded DNA translocase activity for remodeling stalled replication fork by fork reversal, which can support damage bypass by template switching. However, a stalled replication fork is surrounded by various DNA-binding proteins which can inhibit the access of damage bypass players, and it is unknown how these proteins become displaced. Here we reveal that HLTF has an ATP hydrolysis-dependent protein remodeling activity, by which it can remove proteins bound to the replication fork. Moreover, we demonstrate that HLTF can displace a broad spectrum of proteins such as replication protein A (RPA), PCNA, and replication factor C (RFC), thereby providing the first example for a protein clearing activity at the stalled replication fork. Our findings clarify how remodeling of a stalled replication fork can occur if it is engaged in interactions with masses of proteins. U nrepaired DNA lesions are dangerous obstacles for the replication machinery because most of them cannot be accommodated into the active site of the replicative polymerases, thereby blocking the progression of the replication fork. Prolonged stalling might lead to DNA strand breaks, chromosomal rearrangements, or cell death (1-3). To minimize this danger cells have evolved various DNA damage bypass mechanisms that are initiated by exchanging protein components of the normal replication machinery for protein players which either carry out a direct damage bypass or manipulate the stalled fork to generate transitional DNA structures that facilitate damage bypass indirectly. In the first situation, specialized translesion synthesis polymerases that can accommodate even bulky lesions at their active sites take over the 3′ primer end from the accurate replicative polymerase and incorporate either a correct or an incorrect nucleotide opposite the lesion (4, 5). Alternatively, DNA remodeling might lead to the annealing of the stalled nascent strand to the newly synthesized strand of the undamaged sister duplex, resulting in template switch (6-9). Although the exact mechanism and factors of template switch have remained largely unknown, two proposed mechanisms have gained significant attention. One is named-based on the shape of the intermediate DNA structure-chicken foot model, which proposes pairing of the two newly synthesized strands of the sister chromatids by reversal of the stalled fork (9, 10). The other model also suggests pairing of the newly synthesized strands, but assumes that it occurs via a D-loop recombination intermediate (6,(11)(12)(13). It is possible that these mechanisms are not mutually exclusive and the choice can be regulated at the level of displacement and exchange of the protein components of the stalled replication machinery for various new players.It is generally accepted that in eukaryotic cells damage bypass is governed by Rad6 and Rad18, a ubiquitin conjugating and a ...

show abstract

HARPing on about the DNA damage response during replication: Figure 1.

Cited by 34 publications

References 63 publications

Structure of RPA32 bound to the N‐terminus of SMARCAL1 redefines the binding interface between RPA32 and its interacting proteins

Structure of RPA32 bound to the N‐terminus of SMARCAL1 redefines the binding interface between RPA32 and its interacting proteins

SMARCAL1 catalyzes fork regression and Holliday junction migration to maintain genome stability during DNA replication

Coordinated protein and DNA remodeling by human HLTF on stalled replication fork

Contact Info

Product

Resources

About