Chapter category: DNA Surveillance and Repair
Origin, Recognition, Signaling and Repair of DNA Double-Strand Breaks in Mammalian Cells
Eukaryotic DNA Damage Surveillance and Repair
Edited by: Keith W. CaldecottISBN: 0-306-47987-7
» Get more information about this book at landesbioscience.com «
Chapter authors:
Larry H. Thompson and Charles L. Limoli
Achromosomal double-strand break (DSB) can arise from multiple sources including ionizing radiation and DNA replication itself. An understanding of the intricate pro tein pathways that recognize DSBs and recruit the DNA repair and cell cycle checkpoint machinery is developing rapidly. The ATM kinase plays an early, pivotal role in the signaling process by detecting DSBs and relaying this information to numerous downstream transducer and effector proteins. Within minutes after DSBs occur, ATM undergoes inter-molecular autophosphorylation at Ser1981, which converts it to an active monomer. ATMSer1981-P immediately phosphorylates histone H2AX over a megabase region of DNA surrounding a DSB. Discrete nuclear foci of phosphorylated H2AX (gH2AX) are visible by immunofluorescence and appear to be true markers of DSBs. MDC1 and 53BP1, transducer proteins that contain two C-terminal BRCT domains, are also phosphorylated by ATM and colocalize faithfully with gH2AX. Subsequent transducers and effectors include the Mre11-Rad50-NBS1 complex (both transducer and effector), and the breast cancer susceptibility proteins BRCA1 (a transducer) and BRCA2 (an effector). BRCA2 interacts directly with DNA and the Rad51 strand-transferase to help initiate homologous recombination. When the DNA replication machinery is chemically inhibited or encounters a damaged template containing single-strand breaks or blocking lesions, replication forks may arrest, collapse into one-sided DSBs, and require recombinational repair to be reestablished. This recovery process is dependent on the ATR kinase acting in concert with the Rad17-Rfc clamp-loader complex and the Rad9-Rad1-Hus1 clamp complex. Modifiers of DNA topology, such as BLM and WRN helicases associated with Bloom and Werner syndromes, assist in preserving chromosomal continuity during replication. These proteins are thought to resolve anomalous replication intermediates that arise at stalled forks, thereby preventing aberrant recombination for unrepaired DSBs. Overall, the precise nature of a DSB likely determines whether ATM or ATR is utilized to initiate the damage-response pathways.
Additional chapters from this book:
Mammalian Base Excision Repair
Grigory L. Dianov, Sarah L. Allinson, Helen Budworth and Kate Sleeth
In living cells DNA base lesions are formed continuously as a consequence of normal me tabolism and are also generated by a number of external factors. Simple base damages are repaired by base ex...
Origin, Recognition, Signaling and Repair of DNA Double-Strand Breaks in Mammalian Cells
Larry H. Thompson and Charles L. Limoli
Achromosomal double-strand break (DSB) can arise from multiple sources including ionizing radiation and DNA replication itself. An understanding of the intricate pro tein pathways that recognize ...
The Detection and Repair of Nucleotide Damage and Coupling to Major Cellular Regulatory Processes in Mammalian Cells
James E. Cleaver
DNA repair serves to restore two of the main macromolecular functions in the cell: DNA replication and transcription. If either are irrevocably blocked cell death in the form of apoptosis or per...
Mammalian DNA Mismatch Repair
Helen M.R. Robinson and Robert Brown
Some DNA replication errors escape the proof reading activity of DNA polymerases and if allowed to persist will lead to mutations and potential creation of an abnormal mutant cell. Therefore suc...
