DNA replication in the face of (In)surmountable odds.
We describe here a model for sequential recruitment of various enzymatic systems that maintain DNA replication fidelity in cells with damaged bases, especially those formed by ultraviolet (UV) irradiation. Systems of increasing complexity but decreasing fidelity are recruited to restore replication of damaged DNA. The first and most accurate response is nucleotide excision repair (NER) that is cell cycle-independent; next come various delaying cell cycle checkpoints that provide an extended time window for NER. These delay the onset of the S phase at the G1/S boundary, and inhibit the initiation of individual replicating units (replicons and clusters of replicons) within the S phase. When checkpoints fail to operate completely, DNA replication forks must negotiate damage and the loss of coding information on the parental DNA strands. Replication can be resumed using bypass polymerases, or alternative bypass mechanisms. Finally, if all else fails, replication forks may degrade to double strand breaks and recombinational processes then allow their reconstruction. A network of signaling kinases modulates the efficiency of many damage responsive proteins to tailor their activities and subcellular localizations by phosphorylation and dephosphorylation.
Cleaver
J E
JE
Department of Dermatology and UCSF Cancer Center, University of California, San Francisco, California 94143-0808, USA. jcleaver@cc.ucsf.edu
Laposa
R R
RR
Limoli
C L
CL
D000818:Animals; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics / Q000502:physiology*; D004260:DNA Repair / Q000235:genetics / Q000502:physiology*; D004261:DNA Replication / Q000235:genetics / Q000502:physiology*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009154:Mutation; D010766:Phosphorylation; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism; D011995:Recombination, Genetic / Q000235:genetics / Q000502:physiology*; D018741:Replication Origin / Q000235:genetics / Q000502:physiology; D012093:Replicon / Q000235:genetics / Q000502:physiology; D016196:S Phase / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D014466:Ultraviolet Rays
D029742:Caenorhabditis elegans Proteins; D018809:Proliferating Cell Nuclear Antigen; D016159:Tumor Suppressor Protein p53; C423224:mre-11 protein, C elegans; D004259:DNA-Directed DNA Polymerase