BRCA1 activates a G2-M cell cycle checkpoint following 6-thioguanine-induced DNA mismatch damage.

BRCA1 activates a G2-M cell cycle checkpoint following 6-thioguanine-induced DNA mismatch damage. Research Abstract Details 

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BRCA1 activates a G2-M cell cycle checkpoint following 6-thioguanine-induced DNA mismatch damage. Abstract Text:

Kazuhiko Yamane,Jane E Schupp,Timothy J Kinsella,

Human DNA mismatch repair (MMR) is involved in the response to certain chemotherapy drugs, including 6-thioguanine (6-TG). Consistently, MMR-deficient human tumor cells show resistance to 6-TG damage as manifested by a reduced G(2)-M arrest and decreased apoptosis. In this study, we investigate the role of the BRCA1 protein in modulating a 6-TG-induced MMR damage response, using an isogenic human breast cancer cell line model, including a BRCA1 mutated cell line (HCC1937) and its transfectant with a wild-type BRCA1 cDNA. The MMR proteins MSH2, MSH6, MLH1, and PMS2 are similarly detected in both cell lines. BRCA1-mutant cells are more resistant to 6-TG than BRCA1-positive cells in a clonogenic survival assay and show reduced apoptosis. Additionally, the mutated BRCA1 results in an almost complete loss of a G(2)-M cell cycle checkpoint response induced by 6-TG. Transfection of single specific small interfering RNAs (siRNA) against MSH2, MLH1, ATR, and Chk1 in BRCA1-positive cells markedly reduces the BRCA1-dependent G(2)-M checkpoint response. Interestingly, ATR and Chk1 siRNA transfection in BRCA1-positive cells shows similar levels of 6-TG cytotoxicity as the control transfectant, whereas MSH2 and MLH1 siRNA transfectants show 6-TG resistance as expected. DNA MMR processing, as measured by the number of 6-TG-induced DNA strand breaks using an alkaline comet assay (+/-z-VAD-fmk cotreatment) and by levels of iododeoxyuridine-DNA incorporation, is independent of BRCA1, suggesting the involvement of BRCA1 in the G(2)-M checkpoint response to 6-TG but not in the subsequent excision processing of 6-TG mispairs by MMR.

BRCA1 activates a G2-M cell cycle checkpoint following 6-thioguanine-induced DNA mismatch damage. Publishing Authors By Initials

K Yamane,JE Schupp,TJ Kinsella,

For similar investigative techniques: genetic techniques: gene transfer techniques: transfection research abstracts see: investigative techniques: genetic techniques: gene transfer techniques: transfection research

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BRCA1 activates a G2-M cell cycle checkpoint following 6-thioguanine-induced DNA mismatch damage. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: Cancer research

VOLUME: 67

Page Numbers: 6286-92

Journal Abbreviation: Cancer Res.

ISSN: 0008-5472

DAY: 1

MONTH: Jul

YEAR: 2007

BRCA1 activates a G2-M cell cycle checkpoint following 6-thioguanine-induced DNA mismatch damage. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 2984705

BRCA1 activates a G2-M cell cycle checkpoint following 6-thioguanine-induced DNA mismatch damage. Keywords Mesh Terms:

KEYWORDS: Transfection

MESH TERMS: pharmacology

Chemical & Substance for Abstract: BRCA1 activates a G2-M cell cycle checkpoint following 6-thioguanine-induced DNA mismatch damage. Information

Substance Name: Thioguanine

Registry Number: 154-42-7

Grant and Affiliation Information for BRCA1 activates a G2-M cell cycle checkpoint following 6-thioguanine-induced DNA mismatch damage.

AFFILIATION: Department of Radiation Oncology, Case Western Reserve University and Case Comprehensive Cancer Center/University Hospitals Case Medical Center, Cleveland, Ohio 44106-6068, USA.

Country: United States

AGENCY: United States NCI

GRANT: P30 CA43703-12

ACRONYM: CA

MEDLINETA: Cancer Res

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