Article

Cooperation of breast cancer proteins PALB2 and piccolo BRCA2 in stimulating homologous recombination

Genome Stability Laboratory, Laval University Cancer Research Center, Hôtel-Dieu de Québec, Quebec City, Quebec, Canada.
Nature Structural & Molecular Biology (Impact Factor: 13.31). 10/2010; 17(10):1247-54. DOI: 10.1038/nsmb.1915
Source: PubMed

ABSTRACT

Inherited mutations in human PALB2 are associated with a predisposition to breast and pancreatic cancers. PALB2's tumor-suppressing effect is thought to be based on its ability to facilitate BRCA2's function in homologous recombination. However, the biochemical properties of PALB2 are unknown. Here we show that human PALB2 binds DNA, preferentially D-loop structures, and directly interacts with the RAD51 recombinase to stimulate strand invasion, a vital step of homologous recombination. This stimulation occurs through reinforcing biochemical mechanisms, as PALB2 alleviates inhibition by RPA and stabilizes the RAD51 filament. Moreover, PALB2 can function synergistically with a BRCA2 chimera (termed piccolo, or piBRCA2) to further promote strand invasion. Finally, we show that PALB2-deficient cells are sensitive to PARP inhibitors. Our studies provide the first biochemical insights into PALB2's function with piBRCA2 as a mediator of homologous recombination in DNA double-strand break repair.

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Available from: Yan Coulombe, Jul 02, 2014
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    • "Given the promising response of BRCA-mutated breast and ovarian cancers to PARP inhibitors [4] [16], it is of interest to identify additional determinants of PARP inhibitor sensitivity, thereby extending their utility in cancer therapy. Recently, PALB2-, RAD51C-and SLX4-deficiency have been coupled to PARP inhibitor sensitivity [17] [18] [19]. Bi-allelic germ-line mutations in BRCA2, PALB2 or SLX4 cause Fanconi anemia (FA), a genomic instability syndrome characterized by congenital abnormalities, bone marrow failure and a high risk to develop cancer, whereas mutations in RAD51C lead to an FA-like syndrome [20] [21] [22] [23] [24] [25]. "
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    ABSTRACT: The encouraging response rates of BRCA1- and BRCA2-mutated cancers toward PARP inhibitors make it worthwhile to identify other potential determinants of PARP inhibitor responsiveness. Since the Fanconi anemia (FA) pathway coordinates several DNA repair pathways, including homologous recombination in which BRCA1 and BRCA2 play important roles, we investigated whether this pathway harbors other predictors of PARP inhibitor sensitivity. Lymphoblastoid cell lines derived from individuals with FA or clinically related syndromes, such as Warsaw breakage syndrome, were tested for PARP inhibitor sensitivity. Remarkably, we found a strong variability in PARP inhibitor sensitivity among different FANCD1/BRCA2-deficient lymphoblasts, suggesting that PARP inhibitor response depends on the type of FANCD1/BRCA2 mutation. We identified the DNA helicases FANCM and DDX11 as determinants of PARP inhibitor response. These results may extend the utility of PARP inhibition as effective anticancer treatment. Copyright © 2014 Elsevier B.V. All rights reserved.
    Full-text · Article · Dec 2014 · DNA Repair
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    • "Determining PALB2 mutation status is important, however, as it may allow female relatives of mutation positive patients the opportunity to make informed decisions about options to mitigate their elevated risk for disease. Also, new effective targeted therapeutic options are becoming available (PARP inhibitors) that have shown promising results in in vitro studies with PALB2 deficient cells exhibiting a defect in homologous repair [11]. "
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    ABSTRACT: Background PALB2 has emerged as a breast cancer susceptibility gene. Mutations in PALB2 have been identified in almost all breast cancer populations studied to date, but the rarity of these mutations and lack of information regarding their penetrance makes genetic counseling for these families challenging. We studied BRCA1/2 -negative breast and/or ovarian cancer families to a) assess the contribution of PALB2 mutations in this series and b) identify clinical, pathological and family history characteristics that might make PALB2 screening more efficient. Methods The coding region of the PALB2 gene was analyzed in 175 probands with family histories of breast and/or ovarian cancer ascertained from a single Canadian institution in Eastern Ontario. Results We identified 2 probands with PALB2 mutations that are known or strongly considered to be pathogenic and 3 probands with missense mutations that are possibly pathogenic. One of the identified truncating mutations [c.3113G > A (p.Gly1000_Trp1038del – major product)], has been previously described while the other four mutations [c.3507_3508delTC (p.H1170Ffs*19), c.1846G > C (p.D616H), c.3418 T > G (p.W1140G), c.3287A > G (p.N1096S)] have not been previously reported. Loss of heterozygosity was detected in two breast tumors from one c.3507_3508delTC mutation carrier but not in other available tumors from that family or in tumors from carriers of other mutations. Conclusions PALB2 mutation screening identifies a small, but significant number of mutations in BRCA1/2 -negative breast and/or ovarian cancer families. We show that mutations are more likely to be found in families with three or more breast cancers as well as other BRCA2-related cancers. In our cohort, both clearly pathogenic mutations were identified in premenopausal breast cancer cases (2/77, 2.6%). Testing should be preferentially offered to affected women from such families.
    Full-text · Article · Aug 2014 · Hereditary Cancer in Clinical Practice
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    • "The function of PALB2 upstream of RAD51 is also supported by the finding that key regulators of PALB2, including BRCA1 and MRG15, are required for optimal assembly of RAD51 foci[63,65]. Although both RAD51 and BRCA2 can directly bind to the WD40 domain of PALB2[58,68,93], whether they bind simultaneously in a ternary complex has not been determined. This possibility is consistent, however, with the finding that RAD51 and BRCA2 have different patterns of interactions with missense mutants of the PALB2 WD40 domain[58]. "
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    ABSTRACT: PALB2 was first identified as a partner of BRCA2 that mediates its recruitment to sites of DNA damage. PALB2 was subsequently found as a tumor suppressor gene. Inherited heterozygosity for this gene is associated with an increased risk of cancer of the breast and other sites. Additionally, biallelic mutation of PALB2 is linked to Fanconi anemia, which also has an increased risk of developing malignant disease. Recent work has identified numerous interactions of PALB2, suggesting that it functions in a network of proteins encoded by tumor suppressors. Notably, many of these tumor suppressors are related to the cellular response to DNA damage. The recruitment of PALB2 to DNA double-strand breaks at the head of this network is via a ubiquitin-dependent signaling pathway that involves the RAP80, Abraxas and BRCA1 tumor suppressors. Next, PALB2 interacts with BRCA2, which is a tumor suppressor, and with the RAD51 recombinase. These interactions promote DNA repair by homologous recombination (HR). More recently, PALB2 has been found to bind the RAD51 paralog, RAD51C, as well as the translesion polymerase pol η, both of which are tumor suppressors with functions in HR. Further, an interaction with MRG15, which is related to chromatin regulation, may facilitate DNA repair in damaged chromatin. Finally, PALB2 interacts with KEAP1, a regulator of the response to oxidative stress. The PALB2 network appears to mediate the maintenance of genome stability, may explain the association of many of the corresponding genes with similar spectra of tumors, and could present novel therapeutic opportunities.
    Full-text · Article · Jul 2014 · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
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