Review of 53bp1 Inhibitory Mechanism in Homologous Recombination in Brca1-Deficient Cells by Blocking Resection of Dna Breaks and Its Chemotherapeutic Implication
Review of 53BP1 inhibitory mechanism in Homologous Recombination in Brca1-Deficient Cells by Blocking Resection of DNA Breaks and Its Chemotherapeutic Implication
BRCA1 is tumor repressor gene and plays an important role in breast cancer development. In the DNA double-stranded break (DSB) repair, loss of BRCA1 contributes to defective homologous recombination (HR) and predominant non-homologous end-joining (NHEJ), which leads to significant defects in genomic stability with increased amount of radial chromosomes that normally inhibits proliferation (Bunting et al., 2010). For the mice homozygous for null BRCA1 mutations, for example with exon-11 deletion (Δ11) isoform of BRCA1 (BRCA111/11), the organisms develop embryonic lethality, which display severe apoptosis (Liu et al., 1996; Ludwig et al., 1997). As a result, cells must acquire secondary mutations to allow proliferation and tumorigenesis in order to survive with BRCA1 deficiency (Aly and Ganesan, 2011). Almost all BRCA1-deficient cancer cells have acquired p53 mutations, but p53 function is not enough to overcome the growth defect resulted by BRCA1 loss. Losses of p53 can only delays embryonic lethality in full null BRCA1-mutant mice by a few days. Except this aspect, there are still several defects (Aly and Ganesan, 2011). These secondary mutations might interfere with the chemotherapeutic drug, the poly(ADP-ribose) polymerase (PARP) inhibitor, which lead to a great impact in cancer chemotherapy
Cao et al. first found this functional interaction between 53BP1 and BRCA1 by investigating the effect of mutations in other DNA repair and checkpoint proteins on BRCA111/11 mutant cells. 53BP1, a nuclear protein, is the human ortholog of yeast DNA damage checkpoint proteins Rad9p/Crb2, with a key role in DNA repair response and checkpoint control (Cao et al, 2009). Upon the induction of DNA DSBs, 53BP1 rapidly redistributes from a diffuse nuclear localization to discrete foci that co-localize with
BRCA1 is tumor repressor gene and plays an important role in breast cancer development. In the DNA double-stranded break (DSB) repair, loss of BRCA1 contributes to defective homologous recombination (HR) and predominant non-homologous end-joining (NHEJ), which leads to significant defects in genomic stability with increased amount of radial chromosomes that normally inhibits proliferation (Bunting et al., 2010). For the mice homozygous for null BRCA1 mutations, for example with exon-11 deletion (Δ11) isoform of BRCA1 (BRCA111/11), the organisms develop embryonic lethality, which display severe apoptosis (Liu et al., 1996; Ludwig et al., 1997). As a result, cells must acquire secondary mutations to allow proliferation and tumorigenesis in order to survive with BRCA1 deficiency (Aly and Ganesan, 2011). Almost all BRCA1-deficient cancer cells have acquired p53 mutations, but p53 function is not enough to overcome the growth defect resulted by BRCA1 loss. Losses of p53 can only delays embryonic lethality in full null BRCA1-mutant mice by a few days. Except this aspect, there are still several defects (Aly and Ganesan, 2011). These secondary mutations might interfere with the chemotherapeutic drug, the poly(ADP-ribose) polymerase (PARP) inhibitor, which lead to a great impact in cancer chemotherapy
Cao et al. first found this functional interaction between 53BP1 and BRCA1 by investigating the effect of mutations in other DNA repair and checkpoint proteins on BRCA111/11 mutant cells. 53BP1, a nuclear protein, is the human ortholog of yeast DNA damage checkpoint proteins Rad9p/Crb2, with a key role in DNA repair response and checkpoint control (Cao et al, 2009). Upon the induction of DNA DSBs, 53BP1 rapidly redistributes from a diffuse nuclear localization to discrete foci that co-localize with