Expression of human BRCA1δ17-19 alternative splicing variant
with a truncated BRCT domain inMCF-7 cells results in impaired
assembly of DNA repair complexes and aberrant DNA
damageresponse

J 2013

Expression of human BRCA1δ17-19 alternative splicing variant with a truncated BRCT domain inMCF-7 cells results in impaired assembly of DNA repair complexes and aberrant DNA damageresponse

SEVCIK, J, Martin FALK, L MACUREK, P KLEIBLOVA, F LHOTA et. al.

Základní údaje

Originální název

Expression of human BRCA1δ17-19 alternative splicing variant with a truncated BRCT domain inMCF-7 cells results in impaired assembly of DNA repair complexes and aberrant DNA damageresponse

Autoři

SEVCIK, J, Martin FALK, L MACUREK, P KLEIBLOVA, F LHOTA, J HOJNY, L STEFANCIKOVA, M Bartek J JANATOVA, J STRIBRNA, Z HODNY, L JEZKOVA, P POHLREICH a Z KLEIBL

Vydání

Cellular Signalling, Elsevier Science, 2013, 0898-6568

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Stát vydavatele

Česká republika

Utajení

není předmětem státního či obchodního tajemství

Impakt faktor

Impact factor: 4.471

DOI

http://dx.doi.org/10.1016/j.cellsig.2013.02.008

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 19. 12. 2019 13:31, doc. RNDr. Martin Falk, Ph.D.

Anotace

V originále

Alternative pre-mRNA splicing is a fundamental post-transcriptional regulatory mechanism. Cancer-specific misregulation of the splicing process may lead to formation of irregular alternative splicing variants (ASVs) with a potentially negative impact on cellular homeostasis. Alternative splicing of BRCA1 pre-mRNA can give rise to BRCA1 protein isoforms that possess dramatically altered biological activities compared with full-length wild-type BRCA1. During the screening of high-risk breast cancer (BC) families we ascertained numerous BRCA1 ASVs, however, their clinical significance for BC development is largely unknown. In this study, we examined the influence of the BRCA1δ17-19 ASV, which lacks a portion of the BRCT domain, on DNA repair capacity using human MCF-7 BC cell clones with stably modified BRCA1 expression. Our results show that overexpression of BRCA1δ17-19 impairs homologous recombination repair (sensitizes cells to mitomycin C), delays repair of ionizing radiation-induced DNA damage and dynamics of the ionizing radiation-induced foci (IRIF) formation, and undermines also the non-homologous end joining repair (NHEJ) activity. Mechanistically, BRCA1δ17-19 cannot interact with the partner proteins Abraxas and CtIP, thus preventing interactions known to be critical for processing of DNA lesions. We propose that the observed inability of BRCA1δ17-19 to functionally replace wtBRCA1 in repair of DNA double-strand breaks (DDSB) reflects impaired capacity to form the BRCA1-A and -C repair complexes. Our findings indicate that expression of BRCA1δ17-19 may negatively influence genome stability by reducing the DDSB repair velocity, thereby contributing to enhanced probability of cancer development in the affected families.

Návaznosti

GBP302/12/G157, projekt VaV

Název: Dynamika a organizace chromosomů během buněčného cyklu a při diferenciaci v normě a patologii

Investor: Grantová agentura ČR, Dynamika a organizace chromosomů během buněčného cyklu a při diferenciaci v normě a patologii

Citovat

SEVCIK, J, Martin FALK, L MACUREK, P KLEIBLOVA, F LHOTA, J HOJNY, L STEFANCIKOVA, M Bartek J JANATOVA, J STRIBRNA, Z HODNY, L JEZKOVA, P POHLREICH a Z KLEIBL. Expression of human BRCA1δ17-19 alternative splicing variant with a truncated BRCT domain inMCF-7 cells results in impaired assembly of DNA repair complexes and aberrant DNA damageresponse. Cellular Signalling. Elsevier Science, 2013, roč. 25, č. 5, s. 1186-1193. ISSN 0898-6568. Dostupné z: https://dx.doi.org/10.1016/j.cellsig.2013.02.008.

@article{1594221,
   author = {Sevcik, J and Falk, Martin and Macurek, L and Kleiblova, P and Lhota, F and Hojny, J and Stefancikova, L and Janatova, M Bartek J and Stribrna, J and Hodny, Z and Jezkova, L and Pohlreich, P and Kleibl, Z},
   article_number = {5},
   doi = {http://dx.doi.org/10.1016/j.cellsig.2013.02.008},
   language = {eng},
   issn = {0898-6568},
   journal = {Cellular Signalling},
   title = {Expression of human BRCA1δ17-19 alternative splicing variant with a truncated BRCT domain inMCF-7 cells results in impaired assembly of DNA repair complexes and aberrant DNA damageresponse},
   volume = {25},
   year = {2013}
}

TY  - JOUR
ID  - 1594221
AU  - Sevcik, J - Falk, Martin - Macurek, L - Kleiblova, P - Lhota, F - Hojny, J - Stefancikova, L - Janatova, M Bartek J - Stribrna, J - Hodny, Z - Jezkova, L - Pohlreich, P - Kleibl, Z
PY  - 2013
TI  - Expression of human BRCA1δ17-19 alternative splicing variant with a truncated BRCT domain inMCF-7 cells results in impaired assembly of DNA repair complexes and aberrant DNA damageresponse
JF  - Cellular Signalling
VL  - 25
IS  - 5
SP  - 1186-1193
EP  - 1186-1193
PB  - Elsevier Science
SN  - 08986568
N2  - Alternative pre-mRNA splicing is a fundamental post-transcriptional regulatory mechanism. Cancer-specific misregulation of the splicing process may lead to formation of irregular alternative splicing variants (ASVs) with a potentially negative impact on cellular homeostasis. Alternative splicing of BRCA1 pre-mRNA can give rise to BRCA1 protein isoforms that possess dramatically altered biological activities compared with full-length wild-type BRCA1. During the screening of high-risk breast cancer (BC) families we ascertained numerous BRCA1 ASVs, however, their clinical significance for BC development is largely unknown. In this study, we examined the influence of the BRCA1δ17-19 ASV, which lacks a portion of the BRCT domain, on DNA repair capacity using human MCF-7 BC cell clones with stably modified BRCA1 expression. Our results show that overexpression of BRCA1δ17-19 impairs homologous recombination repair (sensitizes cells to mitomycin C), delays repair of ionizing radiation-induced DNA damage and dynamics of the ionizing radiation-induced foci (IRIF) formation, and undermines also the non-homologous end joining repair (NHEJ) activity. Mechanistically, BRCA1δ17-19 cannot interact with the partner proteins Abraxas and CtIP, thus preventing interactions known to be critical for processing of DNA lesions. We propose that the observed inability of BRCA1δ17-19 to functionally replace wtBRCA1 in repair of DNA double-strand breaks (DDSB) reflects impaired capacity to form the BRCA1-A and -C repair complexes. Our findings indicate that expression of BRCA1δ17-19 may negatively influence genome stability by reducing the DDSB repair velocity, thereby contributing to enhanced probability of cancer development in the affected families.
ER  -

SEVCIK, J, Martin FALK, L MACUREK, P KLEIBLOVA, F LHOTA, J HOJNY, L STEFANCIKOVA, M Bartek J JANATOVA, J STRIBRNA, Z HODNY, L JEZKOVA, P POHLREICH a Z KLEIBL. Expression of human BRCA1δ17-19 alternative splicing variant with a truncated BRCT domain inMCF-7 cells results in impaired assembly of DNA repair complexes and aberrant DNA damageresponse. \textit{Cellular Signalling}. Elsevier Science, 2013, roč.~25, č.~5, s.~1186-1193. ISSN~0898-6568. Dostupné z: https://dx.doi.org/10.1016/j.cellsig.2013.02.008.

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