DNA damage response pathways in tumor suppression and cancer treatment.
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 (ATM-Rad3-related) 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 poly(ADP-ribose) polymerase (PARP-1) 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 high-throughput screening to identify novel compounds that specifically target the Brit1-deficient cancer which will lead to development of effective personalized drugs to cure cancer in clinic.
Liang
Yulong
Y
The Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Feigin Center, FC830.29, MC-FC850, 1102 Bates Avenue, Houston, TX 77030, USA.
Lin
Shiaw-Yih
SY
Brunicardi
F Charles
FC
Goss
John
J
Li
Kaiyi
K
D064007:Ataxia Telangiectasia Mutated Proteins; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics; D018797:Cell Cycle Proteins / Q000502:physiology*; D003598:Cytoskeletal Proteins; D004249:DNA Damage / Q000235:genetics / Q000502:physiology*; D004260:DNA Repair / Q000235:genetics / Q000502:physiology*; D049914:DNA Repair-Deficiency Disorders / Q000235:genetics; D004268:DNA-Binding Proteins / Q000502:physiology*; D006801:Humans; D009419:Nerve Tissue Proteins / Q000172:deficiency; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000378:metabolism / Q000502:physiology*
D019313:BRCA1 Protein; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; C460645:MCPH1 protein, human; D009419:Nerve Tissue Proteins; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D025521:Tumor Suppressor Proteins; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases