Nuclear–cytoplasmic shuttling of BARD1 contributes to its proapoptotic activity and is regulated by dimerization with BRCA1

Rodriguez, José Antonio; Schüchner, Stefan; Au, Wendy W.Y.; Fabbro, Megan; Henderson, Beric R.

doi:10.1038/sj.onc.1207302

Cited by 79 publications

(99 citation statements)

References 27 publications

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“…BARD1 is also required for proper localization of BRCA1 to damaged induced foci. This relationship is reciprocal as BRCA1 is required for proper localization of BARD1 (47).…”

Section: Introductionmentioning

confidence: 99%

BRCA1 DNA-Binding Activity Is Stimulated by BARD1

Simons

Horwitz²,

Starita³

et al. 2006

Cancer Research

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The breast-and ovarian-specific tumor suppressor BRCA1 has been implicated in numerous cellular processes, including transcription, ubiquitination, and DNA repair. Its tumor suppression activity is tightly linked to that of BARD1, a protein that heterodimerizes with BRCA1. It has been previously shown that BRCA1 binds to DNA, an interesting functional observation in light of the genetic data linking BRCA1 to DNA repair pathways. In this work, we reexamine the DNA-binding properties of BRCA1, comparing them with the DNA-binding properties of the BRCA1/BARD1 heterodimer. Because nuclear BRCA1 exists as a heterodimer with BARD1, it is likely that in vitro studies of the heterodimer will provide a more accurate model of physiologic conditions. Our results indicate that whereas BARD1 cannot directly bind DNA, it does enhance DNA binding by BRCA1. This is a surprising observation as both DNA-binding domains are distal to the BARD1-interacting RING domain of BRCA1. Further analysis of the dimerization reveals that the BRCA1/ BARD1 interaction is not limited to the amino-terminal RING domains of each protein. The carboxyl terminus of BRCA1 contributes significantly to the stability of the heterodimer. We also show that the presence of BARD1 has a secondary effect, as autoubiquitination of BRCA1/BARD1 heterodimers additionally enhances the affinity of BRCA1 for DNA. Together, these data suggest that BRCA1 and BARD1 heterodimerization is stabilized via domains not previously thought to interact and that BARD1 acts in both ubiquitination-dependent and ubiquitination-independent ways to influence the role of

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“…BARD1 is also required for proper localization of BRCA1 to damaged induced foci. This relationship is reciprocal as BRCA1 is required for proper localization of BARD1 (47).…”

Section: Introductionmentioning

confidence: 99%

BRCA1 DNA-Binding Activity Is Stimulated by BARD1

Simons

Horwitz²,

Starita³

et al. 2006

Cancer Research

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“…Loss of FL BARD1 and expression of isoforms that lack the RING finger and are deficient for BRCA1 interaction (43) entails the loss of BRCA1-BARD1 ubiquitylation functions, which are important for tumor suppressor functions but will also influence BRCA1 stability and/or nuclear localization (44)(45)(46). Therefore, lack of FL BARD1 and expression of isoforms lacking the RING domain could have a similar cancer predisposition effect as mutations in BRCA1 when occurring in healthy tissue.…”

Section: Bard1 Isoforms In Cancermentioning

confidence: 99%

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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“…Recently, it was shown that BRCA1 contains a functional HIV Rev-like NES within its N-terminus (aa 86-95) (Rodriguez and Henderson, 2000;Rodriguez et al, 2004) (see Table 1). This region of BRCA1 also contains a corepressor extended helix-like motif, LxxI(I/ H)xxx(I/L) (Perissi et al, 1999).…”

Section: Role Of Brca1 Nuclear Export Signal (Nes)/ Corepressor-like mentioning

confidence: 99%

Structural determinants of the BRCA1 : estrogen receptor interaction

et al. 2005

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Previously, we showed that the BRCA1 protein interacts directly and functionally with estrogen receptor-alpha (ER-a), resulting in the inhibition of estradiol (E2)-stimulated ER-a transcriptional activity. The interaction sites were mapped to the N-terminus of BRCA1 (within amino acids (aa) 1-302) and the ligand-binding domain/ activation function-2 (LBD/AF-2) region (within aa 282-420) of ER-a. In this study, we have further characterized the structure/function relationship for the BRCA1 : ER-a interaction. We found that the N-terminal RING domain (aa 20-64) is not required for the BRCA1 : ER-a interaction. We identified two separate contact points for ER-a, one within aa 1-100 and the other within aa 100-200 of BRCA1; and we showed that each of these BRCA1 peptides interacts with BRCA1 in vitro and in vivo. By using different fragments of the BRCA1 Nterminus, we found that aa 67-100 and 101-133 are required for the interaction with ER-a, but that aa 1-67 and 134-302 are dispensible. Previously, we showed that BRCA1 aa 1-302 does not inhibit E2-stimulated ER-a transcriptional activity but does bind to ER-a and acts as a dominant negative inhibitor of the full-length BRCA1 protein. Somewhat surprisingly, we found that BRCA1 aa 1-100 and BRCA1 aa 101-200 (but not aa 201-300) each inhibited ER-a activity, although not as efficiently as fulllength BRCA1. Mutations within an HIV Rev-like nuclear export signal that resembles a nuclear receptor corepressor motif (aa 86-95) impaired the ability of both truncated (aa 1-100) and full-length (aa 1-1863) BRCA1 proteins to interact with and/or repress ER-a activity. Based on these findings, a partial BRCA1 : ER-a threedimensional structure is proposed. The implications of these findings for understanding the BRCA1 : ER-a interaction are discussed.

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Nuclear–cytoplasmic shuttling of BARD1 contributes to its proapoptotic activity and is regulated by dimerization with BRCA1

Cited by 79 publications

References 27 publications

BRCA1 DNA-Binding Activity Is Stimulated by BARD1

BRCA1 DNA-Binding Activity Is Stimulated by BARD1

Oncogenic BARD1 Isoforms Expressed in Gynecological Cancers

Structural determinants of the BRCA1 : estrogen receptor interaction

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