Role played by BRCA1 in transcriptional regulation in response to therapy

2007 ◽  
Vol 35 (5) ◽  
pp. 1342-1346 ◽  
Author(s):  
M.M. Murray ◽  
P.B. Mullan ◽  
D.P. Harkin
Keyword(s):  
Cell Cycle ◽  
Transcriptional Regulation ◽  
Cancer Susceptibility ◽  
Susceptibility Gene ◽  
Breast Cancer Susceptibility ◽  
Cell Cycle Checkpoint ◽  
Response To Therapy ◽  
Breast Cancer Susceptibility Gene ◽  
Checkpoint Control ◽  
Cycle Checkpoint

BRCA1 (breast-cancer susceptibility gene 1) is a tumour suppressor, implicated in the hereditary predisposition to breast and ovarian cancer. BRCA1 has been implicated in a number of cellular processes including DNA repair and recombination, cell cycle checkpoint control, chromatin remodelling and ubiquitination. In addition, substantial data now exist to suggest a role for BRCA1 in transcriptional regulation; BRCA1 has been shown to interact with the Pol II holoenzyme complex and to interact with multiple transcription factors, such as p53 and c-Myc. We have previously identified a range of BRCA1 transcriptional targets and have linked these to specific cellular pathways, including cell cycle checkpoint activation and apoptosis. Current research is focused on the transcriptional mechanisms that underpin the association of BRCA1 deficiency with increased sensitivity to DNA damage-based chemotherapy and resistance to spindle poisons.

Che-1/AATF, a multivalent adaptor connecting transcriptional regulation, checkpoint control, and apoptosisThis paper is one of a selection of papers published in this Special Issue, entitled 28th International West Coast Chromatin and Chromosome Conference, and has undergone the Journal's usual peer review process.

2007 ◽  
Vol 85 (4) ◽  
pp. 477-483 ◽  
Author(s):  
Claudio Passananti ◽  
Aristide Floridi ◽  
Maurizio Fanciulli
Keyword(s):  
Cell Cycle ◽  
Transcriptional Regulation ◽  
Rna Polymerase Ii ◽  
Cell Cycle Progression ◽  
Peer Review Process ◽  
Cell Cycle Checkpoint ◽  
Checkpoint Control ◽  
Interacting Protein ◽  
Cycle Checkpoint ◽  
Viral Factor

Che-1/AATF (Che-1) was originally characterized as an interacting protein for RNA polymerase II. In addition to transcriptional regulation, the evidence suggests that Che-1 has a viral factor-like S phase promoting role in counteracting Rb repression to facilitate E2F-dependent transactivation during G1–S transition. Recently, Che-1 was found to play an important role in the DNA damage response and cell-cycle checkpoint control. Genetic studies in mice revealed that Che-1 is essential for preimplantation development and the establishment of embryonic gene expression. Importantly, several findings showed that Che-1 participates in inhibiting apoptotic process. Thus, Che-1 emerges as an important adaptor that connects transcriptional regulation, cell-cycle progression, checkpoint control, and apoptosis.

scholarly journals Brca2 (XRCC11) Deficiency Results in Radioresistant DNA Synthesis and a Higher Frequency of Spontaneous Deletions

2002 ◽  
Vol 22 (2) ◽  
pp. 669-679 ◽  
Author(s):  
Maria Kraakman-van der Zwet ◽  
Wilhelmina J. I. Overkamp ◽  
Rebecca E. E. van Lange ◽  
Jeroen Essers ◽  
Annemarie van Duijn-Goedhart ◽  
...  
Keyword(s):  
Dna Synthesis ◽  
Cancer Susceptibility ◽  
Genome Instability ◽  
Susceptibility Gene ◽  
Chinese Hamster ◽  
Mechanistic Explanation ◽  
Breast Cancer Susceptibility ◽  
Chinese Hamster Cell ◽  
Cell Cycle Checkpoint ◽  
Breast Cancer Susceptibility Gene

ABSTRACT We show here that the radiosensitive Chinese hamster cell mutant (V-C8) of group XRCC11 is defective in the breast cancer susceptibility gene Brca2. The very complex phenotype of V-C8 cells is complemented by a single human chromosome 13 providing the BRCA2 gene, as well as by the murine Brca2 gene. The Brca2 deficiency in V-C8 cells causes hypersensitivity to various DNA-damaging agents with an extreme sensitivity toward interstrand DNA cross-linking agents. Furthermore, V-C8 cells show radioresistant DNA synthesis after ionizing radiation, suggesting that Brca2 deficiency affects cell cycle checkpoint regulation. In addition, V-C8 cells display tremendous chromosomal instability and a high frequency of abnormal centrosomes. The mutation spectrum at the hprt locus showed that the majority of spontaneous mutations in V-C8 cells are deletions, in contrast to wild-type V79 cells. A mechanistic explanation for the genome instability phenotype of Brca2-deficient cells is provided by the observation that the nuclear localization of the central DNA repair protein in homologous recombination, Rad51, is reduced in V-C8 cells.

scholarly journals BRCA1-Dependent Transcriptional Regulation: Implication in Tissue-Specific Tumor Suppression

Cancers ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 513 ◽  
Author(s):  
Xiaowen Zhang ◽  
Rong Li
Keyword(s):  
Transcriptional Regulation ◽  
Germ Line ◽  
Cancer Susceptibility ◽  
Susceptibility Gene ◽  
Breast Cancer Susceptibility ◽  
Breast Cancer Susceptibility Gene ◽  
Dna Double Strand Breaks ◽  
Tissue Specific ◽  
Chromatin Dynamics ◽  
Specific Tumor

Germ-line mutations in breast cancer susceptibility gene 1 (BRCA1) predominantly predispose women to breast and ovarian cancers. BRCA1 is best known for its functions in maintenance of genomic integrity including repairing DNA double-strand breaks through homologous recombination and suppressing DNA replication stress. However, whether these universally important BRCA1 functions in maintenance of genomic stability are sufficient to account for its tissue-specific tumor-suppressing function remains unclear. Accumulating evidence indicates that there are previously underappreciated roles of BRCA1 in transcriptional regulation and chromatin remodeling. In this review, we discuss the functional significance of interactions between BRCA1 and various transcription factors, its role in epigenetic regulation and chromatin dynamics, and BRCA1-dependent crosstalk between the machineries of transcription and genome integrity. Furthermore, we propose a model of how transcriptional regulation could contribute to tissue-dependent tumor-suppressing function of BRCA1.

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