Authors: Yulong Liang ShiawYih Lin F Charles Brunicardi John Goss Kaiyi Li
Publish Date: 2008/11/26
Volume: 33, Issue: 4, Pages: 661-666
Abstract
Mammalian cells are frequently at risk of DNA damage from multiple sources Accordingly cells have evolved the DNA damage response DDR pathways to monitor the integrity of their genome Conceptually DDR pathways contain three major components some with overlapping functions sensors signal transducers and effectors At the level of sensors ATM ataxia telangiectasia mutated and ATR ATMRad3related are proximal kinases that act as the core sensors of and are central to the entire DDR These two kinases function to detect various forms of damaged DNA and trigger DNA damage response cascades If cells harbor DDR defects and fail to repair the damaged DNA it would cause genomic instability and as a result lead to cellular transformation Indeed deficiencies of DDR frequently occur in human cancers Interestingly this property of cancer also provides a great opportunity for cancer therapy For example by using a synthetic lethality model to search for the effective drugs ChK1 inhibitors have been shown to selectively target the tumor cells with p53 mutations In addition the inhibitors of polyADPribose polymerase PARP1 showed selectively killing effects on the cells with defects of homologous recombination HR particularly in the context of BRCA1/2 mutations Since Brit1 is a key regulator in DDR and HR repair we believe that we can develop a similar strategy to target cancers with Brit1 deficiency Currently we are conducting a highthroughput screening to identify novel compounds that specifically target the Brit1deficient cancer which will lead to development of effective personalized drugs to cure cancer in clinicPresented at the Molecular Surgeon Symposium on Personalized Genomic Medicine and Surgery at the Baylor College of Medicine Houston Texas USA April 12 2008 The symposium was supported by a grant from the National Institutes of Health R13 CA132572 to Changyi Chen
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