Review of 53bp1 Inhibitory Mechanism in Homologous Recombination in Brca1-Deficient Cells by Blocking Resection of Dna Breaks and Its Chemotherapeutic Implication

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  • Topic: DNA, DNA repair, P53
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  • Published : January 22, 2013
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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 phosphorylated histone H2AX and other repair proteins including BRCA1. Cells lacking 53BP1 are sensitive to DNA damaging agents and have defects in both S-phase and G2M checkpoints (Mochan et al., 2003). Cao et al found that loss of 53BP1 could completely rescue the BRCA1-deficiency cells from mid-gestational embryonic lethality and tumorigenesis, by which increases the level of HR DSB repair. With further experiment on ES cells with null-allele of Brca1, it extended the founding that loss of 53BP1 could rescue null-mutation of BRCA1 (Cao et al., 2009). Also they observed that loss of 53BP1 alleviated the spontaneous DNA damage, chromosomal abnormalities, and G2/M checkpoint activation associated with loss of BRCA1. Loss of 53BP1, but not p53, reversed the sensitivity of BRCA1-/- cells to cisplatin and mitomycin C. Moreover loss of 53BP1 restored Rad51 foci formation after IR treatment on BRCA1-/- cells, and partly restored HR function in BRCA1-/- as measured by gene targeting (Cao et al., 2009). There are three functions of 53BP1 that we already known; that is, transducing a subset of ATM-dependent cell-cycle checkpoints, facilitating the joining of distal DSBs formed at dysfunction telomeres, and during lymphocyte antigen receptor recombination (Bouwman et al. 2010). However, theses functions of 53BP1 cannot fully explain the mechanism of its reversed Brca1-deficient effect that was illustrated by Cao et al.

In this paper, Bunting et al. focus on the discussion that the BRCA1-deficient cells couldn’t perform the error-free HR on DSB because of the presence of 53BP1, and investigated the possible mechanism of the 53BP1 inhibitory function on HR (Bunting et al., 2010). Their studies showed that 53BP1 could block the resection of DNA ends at DSBs, which is a primary step of HR process. In order to provide evidences for this hypothesis, Bunting et al. firstly illustrated the observed phenomenon of loss of 53BP1, and obtained the evidence that loss of 53BP1 help to relieve...
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