Network architecture of signaling from uncoupled helicase-polymerase to cell cycle checkpoints and trans-lesion DNA synthesis.
When replication is blocked by a template lesion or polymerase inhibitor while helicase continues unwinding the DNA, single stranded DNA (ssDNA) accumulates and becomes coated with RPA, which then initiates signals via PCNA mono-ubiquitination to activate trans-lesion polymerases and via ATR and Chk1 to inhibit Cdk2-dependent cell cycle progression. The signals are conveyed by way of a complex network of molecular interactions. To clarify those complexities, we have constructed a molecular interaction map (MIM) using a novel hierarchical assembly procedure. Molecules were arranged on the map in hierarchical levels according to interaction step distance from the DNA region of stalled replication. The hierarchical MIM allows us to disentangle the network's interlocking pathways and loops and to suggest functionally significant features of network architecture. The MIM shows how parallel pathways and multiple feedback loops can provide failsafe and robust switch-like responses to replication stress. Within the central level of hierarchy ATR and Claspin together appear to function as a nexus that conveys signals from many sources to many destinations. We noted a division of labor between those two molecules, separating enzymatic and structural roles. In addition, the network architecture disclosed by the hierarchical map, suggested a speculative model for how molecular crowding and the granular localization of network components in the cell nucleus can facilitate function.
Kohn
Kurt W
KW
Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA. kohnk@mail.nih.gov
Aladjem
Mirit I
MI
Weinstein
John N
JN
Pommier
Yves
Y
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D064007:Ataxia Telangiectasia Mutated Proteins; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism; D000071877:Checkpoint Kinase 1; D004247:DNA / Q000096:biosynthesis* / Q000378:metabolism; D004249:DNA Damage; D004265:DNA Helicases / Q000378:metabolism*; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism*; D053263:Gene Regulatory Networks; D006801:Humans; D053858:Metabolic Networks and Pathways; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction
D048868:Adaptor Proteins, Signal Transducing; C488158:CLSPN protein, human; D018797:Cell Cycle Proteins; D004247:DNA; D011494:Protein Kinases; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases; D004259:DNA-Directed DNA Polymerase; D004265:DNA Helicases