Conservation of function and primary structure in the BRCA1-associated RING domain (BARD1) protein

Ayi, Teck-Choon; Tsan, Julia Tsou; Hwang, Larn-Yuan; Bowcock, Anne M.; Baer, Richard

doi:10.1038/sj.onc.1202123

Cited by 35 publications

(26 citation statements)

References 28 publications

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“…The expression of BARD1 in most proliferative tissues, particularly in spleen and testis (3,8), is consistent with its role in mitosis. Up-regulated expression of BARD1 was also observed in response to hypoxia, to genotoxic stress (5,9), and to hormone signaling (10), suggesting that up-regulation of BARD1 might be associated with tumor suppressor pathways.…”

Section: Introductionmentioning

confidence: 51%

Oncogenic BARD1 Isoforms Expressed in Gynecological Cancers

et al. 2007

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BARD1 is required for protein stability and tumor suppressor functions of BRCA1, which depend on the ubiquitin ligase activity of the BRCA1-BARD1 heterodimer. The NH 2 -terminal RING domains of both proteins act as interaction modules and form a ubiquitin ligase, which has functions in DNA repair, cell cycle checkpoint regulation, and mitosis. Interestingly, up-regulated expression of truncated BARD1 isoforms was found to be associated with poor prognosis in breast and ovarian cancers and, in a hormonally regulated fashion, in the human cytotrophoblast, a cell type with properties reminiscent of cancer cells. We therefore performed reverse transcription-PCR to determine the structure of BARD1 isoforms in cell lines derived from hormone-dependent and hormoneindependent cancers. We found a specific combination of isoforms, generated by differential splicing and alternative transcription initiation, mostly lacking the BRCA1 interaction domain, in gynecologic but not hematologic cancer cell lines. To investigate the prevalence of BARD1 isoforms in tumors, we applied immunohistochemistry to ovarian cancers, using antibodies distinguishing full-length BARD1 and isoforms. Expression of NH 2 terminally truncated BARD1 was correlated with advanced stage of cancer, and expression of spliced isoforms was typical for clear cell carcinoma, the ovarian cancer with worst prognosis, suggesting a role of BARD1 isoforms in cancer progression. To challenge this hypothesis, we silenced BARD1 isoforms in ovarian cancer cells that lacked wild-type BARD1 by siRNA interference, which led to a complete proliferation arrest. Thus, BARD1 isoform expression is required for cancer cell proliferation, which is compatible with the notion that BARD1 isoforms act as cancer maintenance genes. [Cancer Res 2007;67(24):11876-85]

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Section: Introductionmentioning

confidence: 51%

Oncogenic BARD1 Isoforms Expressed in Gynecological Cancers

et al. 2007

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“…Overall, the human and murine BARD1 proteins are poorly conserved although, like BRCA1, the amount of identity is much higher in specific regions, i.e., the RING, ankyrin, and BRCT domains (1,18). Both mouse Bard1 and frog BARD1 interact with human BRCA1, supporting the high degree of evolutionary conservation observed within the domains that direct heterodimerization (1,22). To assess the ability of human BARD1 to interact and affect the function of mouse Brca1, we expressed FLAG-tagged full-length BARD1 (hBARD1) and an N-terminal BARD1 peptide that is truncated at amino acid 202 (hB202) (Fig.…”

Section: Resultsmentioning

confidence: 99%

BARD1 Participates with BRCA1 in Homology-Directed Repair of Chromosome Breaks

Westermark¹,

Reyngold

Olshen

et al. 2003

Molecular and Cellular Biology

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105

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The BRCA1 tumor suppressor has been implicated in the maintenance of chromosomal stability through homology-directed repair of DNA double-strand breaks. Much of the BRCA1 in cells forms a heterodimeric complex with a structurally related protein BARD1. We report that expression of truncated mouse or human BARD1 peptides capable of interacting with Brca1 results in a homologous-repair deficiency. Repair is mildly reduced in Brca1 wild-type cells and severely reduced in cells that harbor a Brca1 splice product deleted for exon 11. Nuclear localization of the Brca1 or BARD1 peptides is not compromised, implying that the repair deficiency is caused by a more direct effect on repair. The tumor suppressor activity of BRCA1 may require the participation of BARD1 to maintain chromosome integrity through the homologous-repair pathway.

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“…The tissues with the highest expression of BARD1 and BRCA1 mRNAs are spleen and testis (Wu et al, 1996;Ayi et al, 1998;Irminger-Finger et al, 1998). In the spleen, a BRCA1-associated function of BARD1 could be expected, as well as a function in apoptosis.…”

Section: Cytoplasmic Localization Of Bard1mentioning

confidence: 99%

“…BARD1 structurally relates to BRCA1, as it contains N-terminal RING finger and C-terminal BRCT domains (Wu et al, 1996;Ayi et al, 1998); however, novel functions of BARD1 might relate to its ankyrin repeats, which are found in proteins with very diverse functions, and to regions without known protein motifs. Here, we report that BARD1 is found in the nucleus and the cytoplasm and that its apoptotic function is associated with its cytoplasmic localization.…”

Section: Introductionmentioning

confidence: 99%

Nuclear–cytoplasmic translocation of BARD1 is linked to its apoptotic activity

et al. 2004

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The tumor suppressor protein BARD1 plays a dual role in response to genotoxic stress: DNA repair as a BARD1-BRCA1 heterodimer and induction of apoptosis in a BRCA1-independent manner. We have constructed a series of BARD1 deletion mutants and analysed their cellular distribution and capacity to induce apoptosis. As opposed to previous studies suggesting an exclusively nuclear localization of BARD1, we found, both in tissues and cell cultures, nuclear and cytoplasmic localization of BARD1. Enhanced cytoplasmic localization of BARD1, as well as appearance of a 67 kDa C-terminal proteolytic cleavage product, coincided with apoptosis. BARD1 translocates to the nucleus independently of BRCA1. For recruitment to nuclear dots, however, the BRCA1-interacting RING finger domain is required but not sufficient. Protein levels of N-terminal RING finger deletion mutants were much higher than those of fulllength BARD1, despite comparable mRNA levels, suggesting that the N-terminal region comprising the RING finger is important for BARD1 degradation. Sequences required for apoptosis induction were mapped between the ankyrin repeats and the BRCT domains coinciding with two known cancer-associated missense mutations. We suggest that nuclear and cytoplasmic localization of BARD1 reflect its dual function and that the increased cytoplasmic localization of BARD1 is associated with apoptosis.

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Conservation of function and primary structure in the BRCA1-associated RING domain (BARD1) protein

Cited by 35 publications

References 28 publications

Oncogenic BARD1 Isoforms Expressed in Gynecological Cancers

Oncogenic BARD1 Isoforms Expressed in Gynecological Cancers

BARD1 Participates with BRCA1 in Homology-Directed Repair of Chromosome Breaks

Nuclear–cytoplasmic translocation of BARD1 is linked to its apoptotic activity

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