The DNA double-strand break response pathway: becoming more BRCAish than ever.
Breast carcinoma is the leading cause of cancer incidence, and second in cancer mortality to lung cancer, in women of the Western hemisphere. Germ line mutations in the breast cancer susceptibility gene, BRCA1, is responsible for half of all cases of hereditary breast cancer, which constitutes about 5-10% of all cases of breast cancer. Current hypothesis has ascribed a role for Brca1 in maintaining genomic stability, through its involvement in cellular response pathway to the DNA double-strand breaks (DSB). DNA DSB, which are the most deleterious form of DNA damage, are repaired through a series of coordinated steps embedded in a signal transduction pathway that ultimately ensure the elimination of potentially harmful mutations to the genome. This pathway can be crudely divided into a primary and secondary phase. The primary response phase is initiated by sensor proteins that activate transducer protein kinases Atm and Atr, which target downstream effector proteins, such as Chk1 and Chk2, to elicit the secondary response phase. Brca1 has been intimately linked with various aspects of this signaling pathway. However, the precise role of Brca1 in this process remains unclear. In this review, we will provide a simple model in an attempt to clarify the role of Brca1 during cellular response to DNA DSB.
Department of Biological Chemistry, University of California at Irvine, 124 Sprague Hall, Irvine, CA 92697, USA.
Nicholas S Y
NS
Ting
Wen-Hwa
WH
Lee
D000818:Animals; D017209:Apoptosis; D019313:BRCA1 Protein / Q000235:genetics* / Q000502:physiology*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002453:Cell Cycle; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004247:DNA / Q000235:genetics; D004249:DNA Damage; D004260:DNA Repair; D018095:Germ-Line Mutation; D006801:Humans; D008954:Models, Biological; D008957:Models, Genetic; D009154:Mutation; D009369:Neoplasms / Q000235:genetics; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011995:Recombination, Genetic; D015398:Signal Transduction; D014158:Transcription, Genetic
D019313:BRCA1 Protein; D003432:Cross-Linking Reagents; D004247:DNA; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C000605867:CHEK1 protein, human; C578634:CHEK2 protein, human; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases