Regulation of BRCA1, BRCA2 and BARD1 intracellular trafficking

Henderson, Beric R.

doi:10.1002/bies.20277

Cited by 67 publications

(57 citation statements)

References 96 publications

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“…53 It is not immediately clear why loss of cytoplasmic FANCD2 is associated with poor prognosis when FANCD2, and specifically monoubiquitylated FANCD2, is considered to function predominantly in chromatin. However, we note that BRCA1, another protein with ostensibly nuclear functions, shuttles between the nucleus and cytoplasm and has been proposed to have a pro-apoptotic function in the cytoplasm 54 It is possible that the cytoplasmic location of FANCD2 is merely a defect in nuclear uptake/retention so that reduction in cytoplasmic FANCD2 may lead to further reductions in the remaining small, relatively undetectable levels of FANCD2 in the nucleus of the malignant cells, so impairing the FA/BRCA pathway completely. However, the more likely explanation is that non-monoubiquitylated FANCD2 has an alternative protective role in the cytoplasm of cells, such that when it falls below a critical threshold, cancer cells can progress to an aggressive form.…”

Section: Discussionmentioning

confidence: 85%

Significance of the Fanconi Anemia FANCD2 Protein in Sporadic and Metastatic Human Breast Cancer

Rudland

Platt-Higgins

Davies

et al. 2010

The American Journal of Pathology

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FANCD2, a pivotal protein in the Fanconi anemia and BRCA pathway/network, is monoubiquitylated in the nucleus in response to DNA damage. This study examines the subcellular location and relationship with prognostic factors and patient survival of FANCD2 in breast cancer. Antibodies to FANCD2 were used to immunocytochemically stain 16 benign and 20 malignant breast specimens as well as 314 primary breast carcinomas to assess its association with subcellular compartment and prognostic factors using Fisher's Exact test or with patient survival over 20 years using Wilcoxon-Gehan statistics. Immunoreactive FANCD2 was found in the nucleus and cytoplasm of all 16 benign tissues, but nuclear staining was lost from a significant 19/20 malignant carcinomas (P < 0.0001). Antibodies to FANCD2 stained the cytoplasm of 196 primary carcinomas, leaving 118 as negatively stained. Negative cytoplasmic staining was significantly associated with positive staining for the metastasis-inducing proteins S100A4, S100P, osteopontin, and AGR2 (P < 0.002). Survival of patients with FANCD2-negative carcinomas was significantly worse (P < 0.0001) than those with positively stained carcinomas, and only 4% were alive at the census date. Multivariate regression analysis identified negative staining for cytoplasmic FANCD2 as the most significant indicator of patient death (P ‫؍‬ 0.001). Thus FANCD2's cytoplasmic loss in the primary carcinomas may allow the selection of cells overexpressing proteins that can induce metastases before surgery. Previous reports have shown that the expression of four proteins that can induce metastasis in experimental rats are highly significantly correlated with each other and separately with early patient death in human breast cancer. These four proteins are S100A4, osteopontin (OPN), AGR2, and S100P.1-4 If their expression is coordinated, then markers of the underlying mechanism should be even more highly correlated with patient demise. One possible coordination mechanism is the generation of an unstable genome by failure of a DNA repair pathway or some other protective mechanism. The majority of familial breast cancer is associated with individuals heterozygous for the BRCA1 or BRCA2 genes that encode proteins important for the repair of DNA double strand breaks and interstrand crosslinks by homologous recombination. 5,6 Biallelic inactivation of BRCA2 results in one form of the cancer-prone syndrome Fanconi anemia (complementation group FA-D1) and the BRCA2/FANCD1 protein operates with 12 other Fanconi anemia (FA) proteins and BRCA1 in a multifaceted response to DNA damage known as the FA/ BRCA tumor suppressor pathway/network. 7-10 Eight of the 13 proteins, together with two FA-associated-proteins, participate in a nuclear core-complex that is required for the monoubiquitylation of FANCD2 and FANCI.

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Section: Discussionmentioning

confidence: 85%

Significance of the Fanconi Anemia FANCD2 Protein in Sporadic and Metastatic Human Breast Cancer

Rudland

Platt-Higgins

Davies

et al. 2010

The American Journal of Pathology

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“…These nuclear proteins are present in the nucleus, but lack the canonical NLS (NLS1-503KRKRRP508 and NLS2-606PKKNRLRRKS615). This does not exclude the possible indirect transport of BRCA1 when bound to BARD1 or Ubc9 [17,30]. The finding that the 39mer could function as an NLS provides a plausible explanation for the evolutionary retention of this part (39mer) of exon 11 in the two main splice variants of BRCA1 that lack the rest of exon 11.…”

Section: Discussionmentioning

confidence: 95%

Identification of a non-canonical nuclear localization signal (NLS) in BRCA1 that could mediate nuclear localization of splice variants lacking the classical NLS

Korlimarla¹,

Bhandary²,

Prabhu³

et al. 2013

Cellular and Molecular Biology Letters

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The breast cancer type 1 susceptibility gene (BRCA1) is a tumor suppressor gene, mutations or loss of which lead to genomic instability and breast cancer. BRCA1 protein is part of a large multi-protein complex involved in a variety of DNA repair and transcription regulatory functions. At least four splice variants have been described and these differ in their function and tissue and spatio-temporal expression patterns. Structural analysis has revealed the presence of two nuclear localization signals (NLS) located in exon 11 of BRCA1. Interestingly, a splice variant of the protein that lacks both of the known NLS still manages to gain entry to the nucleus. While there is experimental proof for the translocation of these proteins by binding to other established nuclear proteins, we examined the possibility of a hitherto unidentified NLS in this particular variant. In this paper, we present evidence for the existence of a previously unreported non-canonical NLS contained within the first 39 amino acids of exon 11. A fusion protein with this 39mer and a reporter green fluorescent protein translocated into the nucleus when it was expressed in breast epithelial cells. We demonstrate the presence of a hitherto unreported noncanonical NLS in exon 11a of BRCA1. This NLS might aid proteins that were encoded by splice variants and lack the canonical NLS to localize to the nucleus.

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“…One significant factor that regulates the stability of BRCA1 is the protein BARD1. BARD1 associates with BRCA1 to form a RING heterodimer that is essential for its stability, nuclear localization, and E3 ligase activity (9)(10)(11)(12)(13)(14). Each protein controls the abundance and stability of the other in a heterodimerization-dependent manner, and loss of the interaction leads to BRCA1 degradation (9,12).…”

Section: Introductionmentioning

confidence: 99%

HERC2 Is an E3 Ligase That Targets BRCA1 for Degradation

et al. 2010

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The breast cancer suppressor BRCA1 forms a stable heterodimeric E3 ubiquitin ligase with BARD1. Each protein controls the abundance and stability of the other, and loss of the interaction leads to BRCA1 degradation. Here, we show that HERC2, a protein recently implicated in DNA damage repair, targets BARD1-uncoupled BRCA1 for degradation. HERC2 shuttles between the nucleus and the cytoplasm. Its COOH-terminal HECT-containing domain interacts with an NH 2 -terminal degron domain in BRCA1. HERC2 ubiquitinates BRCA1; this reaction depends on Cys 4762 of HERC2, the catalytic ubiquitin binding site, and the degron of BRCA1. The HERC2-BRCA1 interaction is maximal during the S phase of the cell cycle and rapidly diminishes as cells enter G 2 -M, inversely correlated with the steady-state level of BRCA1. Significantly, HERC2 depletion antagonizes the effects of BARD1 depletion by restoring BRCA1 expression and G 2 -M checkpoint activity. Conversely, BARD1 protects BRCA1 from HERC2-mediated ubiquitination. Collectively, our findings identify a function for HERC2 in regulating BRCA1 stability in opposition to BARD1. The HERC2 expression in breast epithelial cells and breast carcinomas suggests that this mechanism may play a role in breast carcinogenesis.Cancer Res; 70(15); 6384-92. ©2010 AACR.

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Regulation of BRCA1, BRCA2 and BARD1 intracellular trafficking

Cited by 67 publications

References 96 publications

Significance of the Fanconi Anemia FANCD2 Protein in Sporadic and Metastatic Human Breast Cancer

Significance of the Fanconi Anemia FANCD2 Protein in Sporadic and Metastatic Human Breast Cancer

Identification of a non-canonical nuclear localization signal (NLS) in BRCA1 that could mediate nuclear localization of splice variants lacking the classical NLS

HERC2 Is an E3 Ligase That Targets BRCA1 for Degradation

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