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Sharan, Shyam K.; Bradley, Allan

doi:10.1023/a:1018788132560

Cited by 11 publications

(2 citation statements)

References 65 publications

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“…In many cases, defects in the mouse and human genes that are homologs of the S. cerevisiae genes identified are associated with genome instability and͞or cancer susceptibility (77,(79)(80)(81)(82)(83)(84)(85)(86)(87). In addition, the proteins encoded by the cancer susceptibility genes BRCA1 and BRCA2 either interact directly with proteins that function in the genome instability suppression pathways described or are phosphorylated by proteins that function in these pathways (24,88,89). The studies presented here have extended the results of previous studies by identifying additional genes that function in suppression of genome instability as well as by further identifying the extensive level of redundancy among the pathways that regulate genome stability.…”

Section: Discussionmentioning

confidence: 61%

Suppression of genome instability by redundant S-phase checkpoint pathways in Saccharomyces cerevisiae

Myung

Kolodner

2002

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

140

106

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Cancer cells show increased genome rearrangements, although it is unclear what defects cause these rearrangements. Previous studies have implicated the Saccharomyces cerevisiae replication checkpoint in the suppression of spontaneous genome rearrangements. In the present study, low doses of methyl methane sulfonate that activate the intra-S checkpoint but not the G 1 or G2 DNA damage checkpoints were found to cause increased accumulation of genome rearrangements in both wild-type strains and to an even greater extent in strains containing mutations causing defects in the intra-S checkpoint. The rearrangements were primarily translocations or events resulting in deletion of a portion of a chromosome arm along with the addition of a new telomere. Combinations of mutations causing individual defects in the RAD24 or SGS1 branches of the intra-S checkpoint or the replication checkpoint showed synergistic interactions with regard to the spontaneous genome instability rate. PDS1 and the RAD50 -MRE11-XRS2 complex were found to be important members of all the S-phase checkpoints in suppressing genome instability, whereas RAD53 only seemed to play a role in the intra-S checkpoints. Combinations of mutations that seem to result in inactivation of the S-phase checkpoints and critical effectors resulted in as much as 12,000 -14,000-fold increases in the genome instability rate. These data support the view that spontaneous genome rearrangements result from DNA replication errors and indicate that there is a high degree of redundancy among the checkpoints that act in S phase to suppress such genome instability. S accharomyces cerevisiae and other organisms contain a number of checkpoints that respond to DNA damage and aberrant DNA structures that occur when DNA replication is blocked. The DNA damage checkpoints in S. cerevisiae result in cell-cycle arrest in either G 1 or G 2 in response to DNA damage during these phases of the cell cycle (1). The DNA damage checkpoint also results in slowing of DNA replication and cell-cycle progression when DNA damage occurs during S phase (2, 3); this latter checkpoint response often is called the intra-S checkpoint. A second checkpoint, sometimes called the replication checkpoint, also functions in S phase to cause cell-cycle arrest and suppression of late replication origins in response to blocked DNA replication (4, 5). Checkpoints are critical for preventing DNA damage-induced genome instability, because they cause cell-cycle delay or arrest in response to DNA damage to allow repair to occur (1, 3, 6, 7). Activation of checkpoints by DNA damage causes activation of signal-transduction pathways resulting in phosphorylation of a number of proteins including recombination and repair proteins as well as increased transcription of a number of genes (8-21). As a result, checkpoints directly target a number of DNA metabolic processes in addition to delaying or arresting cell-cycle progression. Checkpoints also act to prevent spontaneous genome instability (22). The importance of checkpoints in...

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Section: Discussionmentioning

confidence: 61%

Suppression of genome instability by redundant S-phase checkpoint pathways in Saccharomyces cerevisiae

Myung

Kolodner

2002

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

140

106

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“…3 ). Although the structures of BRCA1 and BRCA2 exhibit certain similarities, there is no sequence homology ( 74 , 75 ). Of note, the N-terminal domain, encoded by exons 1-10, spans from amino acids 1-636 and contains a transcription activation domain (TAD) essential for PALB2 binding (21-39 amino acids) ( 76 ).…”

Section: Introductionmentioning

confidence: 99%

Identification of the most common BRCA alterations through analysis of germline mutation databases: Is droplet digital PCR an additional strategy for the assessment of such alterations in breast and ovarian cancer families?

Lavoro

Scalisi²,

Candido

et al. 2022

Int J Oncol

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Breast and ovarian cancer represent two of the most common tumor types in females worldwide. Over the years, several non-modifiable and modifiable risk factors have been associated with the onset and progression of these tumors, including age, reproductive factors, ethnicity, socioeconomic status and lifestyle factors, as well as family history and genetic factors. Of note, BRCA1 and BRCA2 are two tumor suppressor genes with a key role in DNA repair processes, whose mutations may induce genomic instability and increase the risk of cancer development. Specifically, females with a family history of breast or ovarian cancer harboring BRCA1/2 germline mutations have a 60-70% increased risk of developing breast cancer and a 15-40% increased risk for ovarian cancer. Different databases have collected the most frequent germline mutations affecting BRCA1/2. Through the analysis of such databases, it is possible to identify frequent hotspot mutations that may be analyzed with next-generation sequencing (NGS) and novel innovative strategies. In this context, NGS remains the gold standard method for the assessment of BRCA1/2 mutations, while novel techniques, including droplet digital PCR (ddPCR), may improve the sensitivity to identify such mutations in the hereditary forms of breast and ovarian cancer. On these bases, the present study aimed to provide an update of the current knowledge on the frequency of BRCA1/2 mutations and cancer susceptibility, focusing on the diagnostic potential of the most recent methods, such as ddPCR.

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BRCA1 and BRCA2 Mutations in Ovarian Carcinoma

Coukos

Rubin

2003

Diagnosis and Management of Ovarian Disorders

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Untitled

Cited by 11 publications

References 65 publications

Suppression of genome instability by redundant S-phase checkpoint pathways in Saccharomyces cerevisiae

Suppression of genome instability by redundant S-phase checkpoint pathways in Saccharomyces cerevisiae

Identification of the most common BRCA alterations through analysis of germline mutation databases: Is droplet digital PCR an additional strategy for the assessment of such alterations in breast and ovarian cancer families?

BRCA1 and BRCA2 Mutations in Ovarian Carcinoma

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