Colocalization of human Rad17 and PCNA in late S phase of the cell cycle upon replication block

Dahm, Kirsten; Hübscher, Ulrich

doi:10.1038/sj.onc.1205872

Cited by 26 publications

(23 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PCNA is suggested to provide communication between replication checkpoint control and DNA replication and repair [Dahm and FA is required (step 3) for phosphorylation of NBS1, suggesting that monoubiquitination precedes phosphorylation. Hubscher, 2002]. The G2 checkpoint in response to MMC exposure appeared normal in FA-C cells [Heinrich et al, 1998].…”

Section: Linking Nccmentioning

confidence: 99%

How Fanconi anemia proteins promote the four Rs: Replication, recombination, repair, and recovery

Thompson

Hinz

Yamada

et al. 2005

Environ and Mol Mutagen

View full text Add to dashboard Cite

The genetically complex disease Fanconi anemia (FA) comprises cancer predisposition, developmental defects, and bone marrow failure due to elevated apoptosis. The FA cellular phenotype includes universal sensitivity to DNA crosslinking damage, symptoms of oxidative stress, and reduced mutability at the X-linked HPRT gene. In this review article, we present a new heuristic molecular model that accommodates these varied features of FA cells. In our view, the FANCA, -C, and -G proteins, which are both cytoplasmic and nuclear, have an integrated dual role in which they sense and convey information about cytoplasmic oxidative stress to the nucleus, where they participate in the further assembly and functionality of the nuclear core complex (NCCFA= FANCA/B/C/E/F/G/L). In turn, NCCFA facilitates DNA replication at sites of base damage and strand breaks by performing the critical monoubiquitination of FANCD2, an event that somehow helps stabilize blocked and broken replication forks. This stabilization facilitates two kinds of processes: translesion synthesis at sites of blocking lesions (e.g., oxidative base damage), which produces point mutations by error-prone polymerases, and homologous recombination-mediated restart of broken forks, which arise spontaneously and when crosslinks are unhooked by the ERCC1-XPF endonuclease. In the absence of the critical FANCD2 monoubiquitination step, broken replication forks further lose chromatid continuity by collapsing into a configuration that is more difficult to restart through recombination and prone to aberrant repair through nonhomologous end joining. Thus, the FA regulatory pathway promotes chromosome integrity by monitoring oxidative stress and coping efficiently with the accompanying oxidative DNA damage during DNA replication.

show abstract

Section: Linking Nccmentioning

confidence: 99%

How Fanconi anemia proteins promote the four Rs: Replication, recombination, repair, and recovery

Thompson

Hinz

Yamada

et al. 2005

Environ and Mol Mutagen

View full text Add to dashboard Cite

show abstract

“…It is possible that either an unidentified clamp loader is involved, or that the replicative RFC clamp loader itself might be important for the activity of the 9-1-1 complex under some circumstances. Intriguingly, a physical interaction between PCNA and the 9-1-1 clamp has been detected both in vivo and in vitro (55,56). 7 Perhaps when the replicative polymerase and PCNA are stalled at a blocking lesion, the 9-1-1 clamp in conjunction with Pol is targeted to (possibly a modified form of) PCNA, thereby allowing Pol to gain access to the DNA lesion for bypass.…”

Section: Strainmentioning

confidence: 99%

The 9-1-1 Checkpoint Clamp Physically Interacts with Polζ and Is Partially Required for Spontaneous Polζ-dependent Mutagenesis in Saccharomyces cerevisiae

Sabbioneda

Minesinger²,

Giannattasio

et al. 2005

Journal of Biological Chemistry

106

View full text Add to dashboard Cite

The use of translesion synthesis (TLS) polymerases to bypass DNA lesions during replication constitutes an important mechanism to restart blocked/stalled DNA replication forks. Because TLS polymerases generally have low fidelity on undamaged DNA, the cell must regulate the interaction of TLS polymerases with damaged versus undamaged DNA to maintain genome integrity. The Saccharomyces cerevisiae checkpoint proteins Ddc1, Rad17, and Mec3 form a clamp-like structure (the 9-1-1 clamp) that has physical similarity to the homotrimeric sliding clamp proliferating cell nuclear antigen, which interacts with and promotes the processivity of the replicative DNA polymerases. In this work, we demonstrate both an in vivo and in vitro physical interaction between the Mec3 and Ddc1 subunits of the 9-1-1 clamp and the Rev7 subunit of the Pol TLS polymerase. In addition, we demonstrate that loss of Mec3, Ddc1, or Rad17 results in a decrease in Pol-dependent spontaneous mutagenesis. These results suggest that, in addition to its checkpoint signaling role, the 9-1-1 clamp may physically regulate Poldependent mutagenesis by controlling the access of Pol to damaged DNA.The major replicative DNA polymerases are high fidelity enzymes that can be blocked by lesion-containing bases on the template strand (1). Although such blockage can potentially prevent completion of genome duplication, cells can bypass lesions by copying information from the undamaged sister chromatid in a strand switching or recombination type of mechanism. Alternatively, a translesion synthesis (TLS) 5 DNA polymerase can be recruited to insert a nucleotide across from the lesion or to extend a lesion-base mispair (reviewed in Refs. 2 and 3). This unique activity of the TLS polymerases has been attributed to the presence of a large catalytic active site that can accommodate structurally deformed bases (4). Although it has been suggested that each type of translesion polymerase may be specialized to bypass a certain lesion (or class of lesions) in a relatively error-free manner, many of the TLS polymerases exhibit astoundingly low fidelity on undamaged DNA in vitro (reviewed in Refs. 2 and 4). To minimize replication errors on undamaged DNA, the in vivo use of translesion polymerases must be restricted so that they are employed only when needed.Saccharomyces cerevisiae contains three translesion polymerases: Pol, Pol, and Rev1. Pol has been primarily characterized with respect to its role in the error-free bypass of UV-induced lesions (5) and this bypass appears to require physical interaction with PCNA (6). Yeast strains lacking REV1 or Pol demonstrate similar phenotypes in response to DNA damage (4), and it is generally assumed that these two polymerases act in the same pathway of mutagenesis (but see Ref. 7). In vitro studies indicate that Rev1 is a G template-specific DNA polymerase (8), but the relevance of this activity to in vivo mutagenesis is unclear (9). Pol, which is comprised of a catalytic subunit encoded by REV3 and a regulatory subunit encoded by REV7...

show abstract

“…When the replication checkpoint is activated by HU treatment, checkpoint proteins are recruited to the replication fork (51,241). In the absence of the replication checkpoint kinase S. cerevisiae Rad53/S.…”

Section: Mcms and Checkpoint Responsesmentioning

confidence: 99%

“…Its assembly at the origin requires DDK activity, reminiscent of Cdc45. In vertebrate cells, the Rad17 protein, a component of the checkpoint signaling apparatus, associates with early replication foci even in the absence of damage (51), and the Hus1 protein which acts with Rad17 is chromatin associated during normal S phase (356). Thus, interactions between replication and checkpoint proteins may be a normal response to the mutagenic potential of S-phase progression; this is consistent with observations suggesting that S. cerevisiae Mec1 (S. pombe Rad3/human ATR) prevents replication fork stalling (30).…”

Section: Mcms and Checkpoint Responsesmentioning

confidence: 99%

Eukaryotic MCM Proteins: Beyond Replication Initiation

Forsburg

2004

Microbiol Mol Biol Rev

498

506

View full text Add to dashboard Cite

The minichromosome maintenance (or MCM) protein family is composed of six related proteins that are conserved in all eukaryotes. They were first identified by genetic screens in yeast and subsequently analyzed in other experimental systems using molecular and biochemical methods. Early data led to the identification of MCMs as central players in the initiation of DNA replication. More recent studies have shown that MCM proteins also function in replication elongation, probably as a DNA helicase. This is consistent with structural analysis showing that the proteins interact together in a heterohexameric ring. However, MCMs are strikingly abundant and far exceed the stoichiometry of replication origins; they are widely distributed on unreplicated chromatin. Analysis of mcm mutant phenotypes and interactions with other factors have now implicated the MCM proteins in other chromosome transactions including damage response, transcription, and chromatin structure. These experiments indicate that the MCMs are central players in many aspects of genome stability

show abstract

Colocalization of human Rad17 and PCNA in late S phase of the cell cycle upon replication block

Cited by 26 publications

References 44 publications

How Fanconi anemia proteins promote the four Rs: Replication, recombination, repair, and recovery

How Fanconi anemia proteins promote the four Rs: Replication, recombination, repair, and recovery

The 9-1-1 Checkpoint Clamp Physically Interacts with Polζ and Is Partially Required for Spontaneous Polζ-dependent Mutagenesis in Saccharomyces cerevisiae

Eukaryotic MCM Proteins: Beyond Replication Initiation

Contact Info

Product

Resources

About