A Human BRCA2 Complex Containing a Structural DNA Binding Component Influences Cell Cycle Progression

Marmorstein, Lihua Y.; Kinev, Alexander; Chan, Gordon K.; Bochar, Daniel A.; Beniya, Hideo; Epstein, Jonathan A.; Yen, Tim J.; Shiekhattar, Ramin

doi:10.1016/s0092-8674(01)00209-4

Cited by 126 publications

(99 citation statements)

References 36 publications

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“…Interestingly, BRCA2 has been linked to a G 2 /M checkpoint. 66 In these studies, microinjection of BRCA2 antibodies leads to a delay in G 2 /M progression, revealing a potential role for BRCA2 in the timing of mitosis entry. 66 More recently, Brca2 defective Chinese hamster ovary cells have been shown to undergo inappropriate "radioresistant" DNA synthesis suggesting a defect in intra-S phase checkpoints in these cells.…”

Section: Hereditary Breast Cancer and Dna Double Stranded Break Repairmentioning

confidence: 88%

DNA Repair and Tumorigenesis: Lessons from Hereditary Cancer Syndromes

Heinen

Schmütte²,

Fishel³

2002

Cancer Biology & Therapy

108

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The discovery that alterations of the DNA mismatch repair system (MMR) were linked to the common human cancer susceptibility syndrome hereditary nonpolyposis colon cancer (HNPCC) resulted in the declaration of a third class of genes involved in tumor development. In addition to oncogenes and tumor suppressors, alterations of DNA repair genes involved in maintaining genomic stability were found to be a clear cause of tumorigenesis. Nearly all tumors display some form of genomic instability, whether it is on the level of the single nucleotides or chromosomes. This observation suggested that the establishment of genomic instability, termed the Mutator Phenotype, was an important aspect of tumor development.

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Section: Hereditary Breast Cancer and Dna Double Stranded Break Repairmentioning

confidence: 88%

DNA Repair and Tumorigenesis: Lessons from Hereditary Cancer Syndromes

Heinen

Schmütte²,

Fishel³

2002

Cancer Biology & Therapy

108

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“…The role of the HMG domain of Braf35 is less clear. Braf35 HMG domain binds structured DNA, such as four-way junction DNA, without sequence specificity (10). The Shiekhattar group reported that a point mutation in the HMG domain of Braf35 abrogates binding of this protein to its target genes, suggesting that the DNA-binding activity of Braf35 is important for its function (7).…”

Section: Discussionmentioning

confidence: 99%

“…In addition to LSD1 and CoREST, the LSD1-CoREST complex also contains HDAC1-2, BHC80, and BRAF35 (also called HMG20B) (6)(7)(8)(9). BRAF35 contains a high-mobility group (HMG) domain and a coiled-coil domain, but its function within the complex is not well-understood (7,10). Several functions of the LSD1-CoREST complex in differentiation and development have been reported (2).…”

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confidence: 99%

Control of neuronal differentiation by sumoylation of BRAF35, a subunit of the LSD1-CoREST histone demethylase complex

Ceballos-Chávez

Rivero

García-Gutiérrez³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The LSD1-CoREST histone demethylase complex is required to repress neuronal genes in nonneuronal tissues. Here we show that sumoylation of Braf35, one of the subunits of the complex, is required to maintain full repression of neuron-specific genes and for occupancy of the LSD1-CoREST complex at its gene targets. Interestingly, expression of Braf35 was sufficient to prevent neuronal differentiation induced by bHLH neurogenic transcription factors in P19 cells and in neuronal progenitors of the chicken embryo neural tube. Sumoylation of Braf35 is required for this antineurogenic activity. We also show that iBraf, a paralogue of Braf35, forms heterodimers with Braf35. Braf35-iBraf heterodimerization impairs Braf35 interaction with the LSD1-CoREST complex and inhibits Braf35 sumoylation. Consistent with these results, iBraf prevents the antineurogenic activity of Braf35 in vivo. Our data uncover a mechanism of regulation of the LSD1-CoREST complex and provide a molecular explanation for the antagonism between Braf35 and iBraf in neuronal differentiation.C ell differentiation involves large modifications of gene expression that require extensive changes of chromatin epigenetic marks (1). Epigenetic marks are DNA or histone posttranslational modifications that are inherited through cell division and that inform about the transcriptional state of loci. Among histone modifications, histone lysine methylation is of particular interest in development for the broad range of processes in which it is involved, including maintenance of stem cell pluripotency, germ-line determination, cell differentiation, control of HOX genes expression, and so forth (2, 3). Histone lysine methylation was considered a stable posttranslational modification until the discovery of histone demethylases. LSD1/KDM1 (lysine-specific demethylase 1) was the first demethylase identified and catalyzes demethylation of both di-and monomethylated lysine 4 (K4) or lysine 9 (K9) of histone H3 (H3K4me2/1 or H3K9me2/1) (4, 5). The lysine specificity of LSD1 seems to depend on its molecular partners. Thus, when LSD1 is associated with CoREST in the LSD1-CoREST corepressor complex (also called BHC, BRAF-histone deacetylase complex), the preferred substrate is H3K4me2/1, consistent with the fact that methylation of H3K4 is a mark of transcriptionaly active genes. In addition to LSD1 and CoREST, the LSD1-CoREST complex also contains HDAC1-2, BHC80, and BRAF35 (also called HMG20B) (6-9). BRAF35 contains a high-mobility group (HMG) domain and a coiled-coil domain, but its function within the complex is not well-understood (7, 10). Several functions of the LSD1-CoREST complex in differentiation and development have been reported (2). One of the best-characterized functions of the complex is its role in repression of neuronal genes in nonneuronal tissues and neuronal progenitors through its interaction with repressor factor REST (RE1 silencing transcription factor) (11,12). iBRAF (inhibitor of BRAF35, also called HMG20A) is a close paralogue of BRAF35 (13). As BRAF35...

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“…BRCA2 has also been found to associate with known mitotic checkpoint proteins, such as hBUBR1 (Futamura et al, 1531), and with new proteins, such as BRAF35, in close association with phosphorylated histone H3 (Marmorstein et al, 2001). The S phase checkpoint was also found to be defective in a Chinese hamster ovary cell line mutant, recently found to be defective in BRCA2 (Kraakman-van der Zwet et al, 2002).…”

Section: Cell Cycle Checkpointsmentioning

confidence: 99%

Roles of BRCA1 and BRCA2 in homologous recombination, DNA replication fidelity and the cellular response to ionizing radiation

2003

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Inheritance of one defective copy of either of the two breast cancer susceptibility genes, BRCA1 and BRCA2, predisposes individuals to breast and ovarian cancers. Current progress in determining the function of these genes suggests that they participate in a common pathway to facilitate orderly homologous recombination and thereby maintain genomic integrity. As a consequence of this defect in homologous recombination, tumors that arise in BRCA carriers are likely to be more sensitive to ionizing radiation. This review summarizes recent investigations about the nature of the defect in DNA repair, and highlights the unanswered questions about the tumor suppressor paradox of BRCA genes. The unsolved mystery is the other genetic changes that must occur to turn a BRCA-deficient cell from a nonviable cell into a tumor cell capable of endless growth.

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A Human BRCA2 Complex Containing a Structural DNA Binding Component Influences Cell Cycle Progression

Cited by 126 publications

References 36 publications

DNA Repair and Tumorigenesis: Lessons from Hereditary Cancer Syndromes

DNA Repair and Tumorigenesis: Lessons from Hereditary Cancer Syndromes

Control of neuronal differentiation by sumoylation of BRAF35, a subunit of the LSD1-CoREST histone demethylase complex

Roles of BRCA1 and BRCA2 in homologous recombination, DNA replication fidelity and the cellular response to ionizing radiation

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