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Uncoupling of RAD51...
Uncoupling of RAD51 focus formation and cell survival after replication fork stalling in RAD51D null CHO cells
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- Urbin, Salustra (författare)
- Lawrence Livermore Natl. Laboratory, Biosciences and Biotechnology Division
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- Elvers, Ingegerd (författare)
- Stockholms universitet,Institutionen för genetik, mikrobiologi och toxikologi,Thomas Helleday
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- Hinz, John (författare)
- Washington State University, School of Molecular biosciences
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- Helleday, Thomas (författare)
- Stockholms universitet,Institutionen för genetik, mikrobiologi och toxikologi,Thomas Helleday
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- Thompson, Larry (författare)
- Lawrence Livermore Natl. Laboratory, Biosciences and Biotechnoogy Division
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visa färre...
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Lawrence Livermore Natl Laboratory, Biosciences and Biotechnology Division Institutionen för genetik, mikrobiologi och toxikologi (creator_code:org_t)
- Engelska.
- Relaterad länk:
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https://urn.kb.se/re...
Abstract
Ämnesord
Stäng
- In vertebrate cells the five RAD51 paralogs (XRCC2/3, RAD51B/C/D) enhance the efficiency of homologous reocmbination repair (HRR). Stalling and breakage of DNA replication forks is a common event in the large genomes of higher eukaryotes. When cells are exposed to agents that arrest DNA replicaiton, such as hydroxyurea or aphidicolin, fork breakage can lead to chromosomal aberrations and cell killing. We assessed the contribution of the HRR protein RAD51D in resistance to killing by replication-associated DSBs. In repsonse to hydroxyurea, the isogenic rad51d null CHO mutant fails to show any indication of HRR initiation, as assessed by induction of RAD51 foci, as expected. Surprisingly, these cells have normal resistance to killing by replication inhibition from either hydroxyurea or aphidicolin, but show the expected sensitivity to camptothecin, which also generates replication-dependent DSBs. In contrast, we confirm that the V79 xrcc2 mutant does show increased sensitivity to hydroxyurea under some conditinos, which was correlated to its attenuated RAD51 focus response. In response to a PARP1 inhibitor PARP1, rad51d cells, like other HRR mutants, show exquisite sensitivity (>1000 fold), which is also associated with defective RAD51 focus formation. Thus, rad51d cells are broadly deficient in RAD51 focus formation in response to various agents, but this defect is not invariably associated with increased sensitivity. Our results indicate that RAD51 paralogs do not contribute equally to cellular resistance of inhibitors of DNA replication, and that the RAD51 foci associated with replication inhibition may not be a reliable indicator of cellular resistance to such agents.
Nyckelord
- NATURAL SCIENCES
- NATURVETENSKAP
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- art (ämneskategori)
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