Independence of R/M/N Focus Formation and the Presence of Intact BRCA1

Wu, Xiaohua; Petrini, John H.J.; Heine, Walter F.; Weaver, David T.; Livingston, David M.; Chen, Junjie

doi:10.1126/science.289.5476.11a

Cited by 56 publications

(35 citation statements)

References 12 publications

(4 reference statements)

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“…Thus, one of the major unknowns to solve is how BRCA1 recruits BRCA2 and Rad51 while also influencing the behavior of the MRN complex. The relationship between BRCA1 function and the appearance of Rad50 nuclear protein foci has been controversial, with reports showing that BRCA1 was required for the formation Rad50 nuclear protein foci and other reports saying there was no such relationship (41)(42)(43). We reported that loss of function of BRCA1 resulted in more Mre11 foci after homologous recombination and that complementation of BRCA1 inhibited their formation (22).…”

Section: Brca1 and Homologous Recombinationmentioning

confidence: 73%

The Role of the BRCA1 Tumor Suppressor in DNA Double-Strand Break Repair

Zhang

Powell

2005

Molecular Cancer Research

182

154

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The tumor suppressor gene BRCA1 was cloned in 1994 based on its linkage to early-onset breast and ovarian cancer. Although the BRCA1 protein has been implicated in multiple cellular functions, the precise mechanism that determines its tumor suppressor activity is not defined. Currently, the emerging picture is that BRCA1 plays an important role in maintaining genomic integrity by protecting cells from double-strand breaks (DSB) that arise during DNA replication or after DNA damage. The DSB repair pathways available in mammalian cells are homologous recombination and nonhomologous end-joining. BRCA1 function seems to be regulated by specific phosphorylations in response to DNA damage and we will focus this review on the roles played by BRCA1 in DNA repair and cell cycle checkpoints. Finally, we will explore the idea that tumor suppression by BRCA1 depends on its control of DNA DSB repair, resulting in the promotion of error-free and the inhibition of error-prone recombinational repair.

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Section: Brca1 and Homologous Recombinationmentioning

confidence: 73%

The Role of the BRCA1 Tumor Suppressor in DNA Double-Strand Break Repair

Zhang

Powell

2005

Molecular Cancer Research

182

154

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“…From previous reports, MRE11-RAD50-NBS1 complex seems to be a key factor for repair of DNA double-strand break and blocked replication fork by modulating related proteins, including BRCA1 and WRN. In response to ␥-irradiation, BRCA1 and MRE11-RAD50-NBS1 cooperate with each other to form irradiation-induced foci (IRIF) (Wu et al, 2000;Zhong et al, 1999). WRN also interacts with the complex, and hydrourea-induced foci of WRN was shown to be dependent on NBS1 (Cheng et al, 2004;Franchitto and Pichierri, 2004;Pichierri and Franchitto, 2004).…”

Section: Discussionmentioning

confidence: 99%

Accumulation of Werner protein at DNA double-strand breaks in human cells

Lan

Nakajima

Komatsu

et al. 2005

Journal of Cell Science

123

110

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Werner syndrome is an autosomal recessive accelerated-aging disorder caused by a defect in the WRN gene, which encodes a member of the RecQ family of DNA helicases with an exonuclease activity. In vitro experiments have suggested that WRN functions in several DNA repair processes, but the actual functions of WRN in living cells remain unknown. Here, we analyzed the kinetics of the intranuclear mobilization of WRN protein in response to a variety of types of DNA damage produced locally in the nucleus of human cells. A striking accumulation of WRN was observed at laser-induced double-strand breaks, but not at single-strand breaks or oxidative base damage. The accumulation of WRN at double-strand breaks was rapid, persisted for many hours, and occurred in the absence of several known interacting proteins including polymerase β, poly(ADP-ribose) polymerase 1 (PARP1), Ku80, DNA-dependent protein kinase (DNA-PKcs), NBS1 and histone H2AX. Abolition of helicase activity or deletion of the exonuclease domain had no effect on accumulation, whereas the presence of the HRDC (helicase and RNaseD C-terminal) domain was necessary and sufficient for the accumulation. Our data suggest that WRN functions mainly at DNA double-strand breaks and structures resembling double-strand breaks in living cells, and that an autonomous accumulation through the HRDC domain is the initial response of WRN to the double-strand breaks.

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“…However, another study challenged the view that phosphorylated CtIP dissociates from BRCA1 as a mechanism of BRCA1 induction of DNA damage response genes (Wu-Baer and Baer, 2001). Recent studies suggest that in response to double-strand DNA breaks (DSBs) induced by IR, BRCA1 translocates to subnuclear foci (''dots'') containing Mre11, hRad50, and p95NBS1 (Niejemen breakage syndrome protein) (Zhong et al, 1999;Wu et al, 2000), an enzyme complex implicated in DSB repair. BRCA1 can bind directly to DNA, particularly to branched DNA structures, where it inhibits the nucleolytic activity of the Mre11-hRad50-p95NBS1 (Paull et al, 2001).…”

Section: Functional Activities Of Brca1 Cell Cycle Regulation and Gromentioning

confidence: 99%

BRCA1 gene in breast cancer

Rosen

Fan

Pestell

et al. 2003

Journal Cellular Physiology

233

195

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The BRCA1 gene was identified and cloned in 1994 based on its linkage to early onset breast cancer and breast-ovarian cancer syndromes in women. While inherited mutations of BRCA1 are responsible for about 40-45% of hereditary breast cancers, these mutations account for only 2-3% of all breast cancers, since the BRCA1 gene is rarely mutated in sporadic breast cancers. However, BRCA1 expression is frequently reduced or absent in sporadic cancers, suggesting a much wider role in mammary carcinogenesis. Since BRCA1 was cloned in 1994, its molecular function has been the subject of intense investigation. These studies have revealed multiple functions of the BRCA1 that may contribute to its tumor suppressor activity, including roles in: cell cycle progression, several highly specialized DNA repair processes, DNA damage-responsive cell cycle checkpoints, regulation of a set of specific transcriptional pathways, and apoptosis. Many of these functions are linked to protein:protein interactions involving different portions of the 1,863 amino acid (aa) BRCA1 protein. BRCA1 functions in cell cycle progression and the DNA damage response appear to be regulated by distinct and specific phosphorylation events, but the molecular pathways activated by these phosphorylations are only beginning to be unraveled. In addition, the reason that BRCA1 mutation carriers develop specific tumor types (breast and ovarian cancers in women and possibly prostate cancers in men) is not clearly understood. Elucidation of the precise molecular functions of the BRCA1 gene product will greatly enhance our understanding of the pathogenesis of hereditary as well as sporadic mammary carcinogenesis.

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Independence of R/M/N Focus Formation and the Presence of Intact BRCA1

Cited by 56 publications

References 12 publications

The Role of the BRCA1 Tumor Suppressor in DNA Double-Strand Break Repair

The Role of the BRCA1 Tumor Suppressor in DNA Double-Strand Break Repair

Accumulation of Werner protein at DNA double-strand breaks in human cells

BRCA1 gene in breast cancer

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