Stalling of DNA replication fork and RPA binding

Stable Identifier
R-HSA-176175
Type
Reaction [binding]
Species
Homo sapiens
Compartment
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When a DNA replication fork encounters DNA lesions (e.g., cyclobutane pyrimidine dimers or alkylated bases) stalling of the replicative DNA polymerase may occur. This can lead to dissociation or 'uncoupling' of the DNA polymerase from the DNA helicase and generation of long regions of persistent ssDNA. Uncoupling can also occur in response to other genotoxic stresses such as reduced dNTP pools caused by hydroxyurea treatment which inhibits cellular ribonucleotide diphosphate reductase. The exposed ssDNA is bound by the single-stranded DNA binding protein RPA. The persistent nature of this RPA-ssDNA complex (as opposed to a more-transient complex found at an active replication fork) allows it to serve as a signal for replication stress that can be recognized by the ATR-ATRIP and Rad17-Rfc2-5 complexes.

RPA associates with ssDNA in distinct complexes that can be distinguished by the length of ssDNA occluded by each RPA molecule. These complexes reflect the progressive association of distinct DNA-binding domains present in the RPA heterotrimeric structure. Binding is coupled to significant conformational changes within RPA that are observable at the microscopic level. Presumably, the different conformations of free and ssDNA-bound RPA allow the protein to selectively interact with factors such as ATR-ATRIP when bound to DNA.

Literature References
PubMed ID Title Journal Year
15833913 Functional uncoupling of MCM helicase and DNA polymerase activities activates the ATR-dependent checkpoint

Byun, TS, Pacek, M, Yee, MC, Walter, JC, Cimprich, KA

Genes Dev 2005
10051570 Nuclear foci of mammalian recombination proteins are located at single-stranded DNA regions formed after DNA damage

Raderschall, E, Golub, EI, Haaf, T

Proc Natl Acad Sci U S A 1999
8196638 Human replication protein A binds single-stranded DNA in two distinct complexes

Blackwell, LJ, Borowiec, JA

Mol Cell Biol 1994
10373362 Analysis of DNA replication forks encountering a pyrimidine dimer in the template to the leading strand

Cordeiro-Stone, M, Makhov, AM, Zaritskaya, LS, Griffith, JD

J Mol Biol 1999
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