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Details on Person When a DNA replication fork encounters DNA lesions (e.g., cy...

Class:IdSummation:176300
_displayNameWhen a DNA replication fork encounters DNA lesions (e.g., cy...
_timestamp2006-03-11 18:36:03
created[InstanceEdit:176246] D'Eustachio, P, 2006-03-03 16:44:08
literatureReference[LiteratureReference:176190] Functional uncoupling of MCM helicase and DNA polymerase activities activates the ATR-dependent checkpoint
[LiteratureReference:176286] Fork reversal and ssDNA accumulation at stalled replication forks owing to checkpoint defects
[LiteratureReference:176362] Analysis of DNA replication forks encountering a pyrimidine dimer in the template to the leading strand
[LiteratureReference:176241] Multiple mechanisms control chromosome integrity after replication fork uncoupling and restart at irreparable UV lesions
[LiteratureReference:69372] Replication protein A (RPA): the eukaryotic SSB.
[LiteratureReference:69370] Replication protein A: a heterotrimeric, single-stranded DNA-binding protein required for eukaryotic DNA metabolism
[LiteratureReference:176216] Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes
modified[InstanceEdit:176809] D'Eustachio, P, 2006-03-11 18:35:59
textWhen 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.

(summation)[Reaction:176175] Stalling of DNA replication fork and RPA binding [Homo sapiens]
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