BRCA1 Effects on the Cell Cycle and the DNA Damage Response Are Linked to Altered Gene Expression

MacLachlan, Timothy K.; Somasundaram, Kumaravel; Sgagias, Magdalene K.; Shifman, Yelena; Muschel, Ruth J.; Cowan, Kenneth H.; El‐Deiry, Wafik S.

doi:10.1074/jbc.275.4.2777

Cited by 209 publications

(202 citation statements)

References 49 publications

(73 reference statements)

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“…Previous research has shown that BRCA1 protein increases arrest in the cell cycle progression of cells [24]. In addition, BRCA1 protein is reported to indicate the positively regulated expression of CCND1 [25], PCNA [26], NEK2 [27] and MAD2L1 [28]. In the present cell system, cell cycle-related genes, especially those participating in this genetic network (Fig.…”

Section: Discussionsupporting

confidence: 52%

Genetic networks responsive to sodium butyrate in colonic epithelial cells

et al. 2006

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We performed microarray and computational gene network analyses to identify the detailed mechanisms by which sodium butyrate (SB) induces cell growth arrest and the differentiation of mouse colonic epithelial MCE301 cells. Two thousand six hundred four differentially expressed probe sets were identified in the cells treated with 2 mM SB and were classified into four groups. Of these, the gradually increased group and the gradually and remarkably decreased group contained the genetic networks for cellular development and cell cycles or canonical pathways for fatty acid biosynthesis and pyrimidine metabolism, respectively. The present results provide a basis for understanding the detailed molecular mechanisms of action of SB in colonic epithelial cells.

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Section: Discussionsupporting

confidence: 52%

Genetic networks responsive to sodium butyrate in colonic epithelial cells

et al. 2006

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“…While there is good evidence that BRCA1 influences DNA repair through association with repair proteins such as MRE11, RAD50, the BASC or BACH1, 2-4 our studies reveal a BRCA1-mediated transcriptional response leading directly to repair of DNA damage. This is also in contrast to a prevailing view that transcriptional responses by p53 or BRCA1 lead to cell cycle arrest [50][51] which allows time for repair of damage prior to continued DNA replication (i.e., a less direct connection between transcription and repair). Because DDB2 is mutated in XPE, a cancer predisposing syndrome, a link between DDB2 loss-of-function and tumor susceptibility in the case of BRCA1-associated breast and ovarian cancer may exist and is worth investigating.…”

Section: Discussioncontrasting

confidence: 49%

BRCA1 Transcriptionally Regulates Damaged DNA Binding Protein (DDB2) In the DNA Repair Response Following UV-Irradiation

Takimoto¹,

MacLachlan²,

Dicker³

et al. 2002

Cancer Biology & Therapy

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© 2 0 0 2 L a n d e s B i o s c i e n c e . N o t f o r d i s t r i b u t i o n .[Cancer Biology & ABSTRACTThe p53 and BRCA1 tumor suppressors are involved in repair processes and may cooperate to transactivate certain genes, including p21WAF1/CIP1 and GADD45. We find that the Xeroderma Pigmentosum Complementation group E (XPE) mutated Damaged-DNA binding protein p48 (DDB2) is upregulated by BRCA1 in a p53-dependent manner following UVC, Adriamycin, or Cisplatin exposure. BRCA1 enhances p53 binding to the DDB2 promoter in vivo as well as p53-dependent transactivation of DDB2 promoterreporter constructs through a classical p53 DNA responsive element. Antisense abrogation of BRCA1 expression abrogates upregulation of DDB2 after UVC or cisplatin exposure. Using a host cell reactivation assay, DNA repair activity is more significantly restored by introduction of BRCA1 into wt as compared to DDB2-deficient cells. Furthermore disappearance of the photoproducts cyclobutane pyrimidine dimer (CPD) and 6-4 photoproduct (6-4PP) was delayed by antisense abrogation of BRCA1 expression in UV-exposed human cells. Thus the DNA repair function of BRCA1 may be attributed in part to p53-dependent transcriptional induction of DDB2. Loss of BRCA1-dependent DDB2 repair function may contribute to cancer susceptibility and cellular sensitivity to DNA damage.

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“…Overexpression of BRCA1 caused transcriptional stimulation of the DNA damage-responsive gene GADD45 (Harkin et al, 1999). Studies involving high-density cDNA array screening identified many genes, including GADD45, as BRCA1-regulated genes (MacLachlan et al, 2000). Induction of BRCA1 triggers apoptotic response in U2OS correlated well with activation of c-Jun Nterminal kinase/stress-activated protein kinase (JNK/ SAPK) a signaling pathway potentially linked to GADD45 gene family members.…”

Section: Introductionmentioning

confidence: 99%

Caspase-3 mediated cleavage of BRCA1 during UV-induced apoptosis

Zhan

Jin

et al. 2002

Oncogene

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The breast cancer suppressor protein, BRCA1 plays an important role in mediating cell cycle arrest, apoptosis and DNA responses to DNA damage signals. In this study, we show that BRCA1 level is downregulated during UV-induced apoptosis by caspase-3 mediated cleavage. Cleavage of BRCA1 by caspase-3 produced a fragment that contained the C-terminal of the molecule. Accordingly, treatment of cells with caspase-3 inhibitor or mutation of a specific caspase-3 cleavage site (DLLD) at amino acid 1151 -1154 of BRCA1 abolished cleavage and consequential accumulation of the BRCA1 Cterminal fragment. Whereas expression of the noncleavable BRCA1 (D/A 1154) mutant conferred the resistance phenotype to UV-induced cell death, expression of the cleaved BRCA1 C-terminus induced cell death in the absence of UV. Examination of the mechanism of C-terminus-induced cell death revealed that the cleaved fragment triggers the apoptotic response through activation of BRCA1 downstream effectors, GADD45 and JNK. Altogether, results of our study demonstrate a functional role for caspase-3 mediated cleavage of BRCA1 during UV-induced apoptosis.

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BRCA1 Effects on the Cell Cycle and the DNA Damage Response Are Linked to Altered Gene Expression

Cited by 209 publications

References 49 publications

Genetic networks responsive to sodium butyrate in colonic epithelial cells

Genetic networks responsive to sodium butyrate in colonic epithelial cells

BRCA1 Transcriptionally Regulates Damaged DNA Binding Protein (DDB2) In the DNA Repair Response Following UV-Irradiation

Caspase-3 mediated cleavage of BRCA1 during UV-induced apoptosis

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