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The Bloom's syndrome helicase interacts directly with the human DNA mismatch repair protein hMSH6


Pedrazzi, G; Bachrati, C Z; Selak, N; Studer, I; Petkovic, M; Hickson, I D; Jiricny, J; Stagljar, I (2003). The Bloom's syndrome helicase interacts directly with the human DNA mismatch repair protein hMSH6. Biological Chemistry, 384(8):1155-1164.

Abstract

Bloom's syndrome (BS) is a rare genetic disorder characterised by genome instability and cancer susceptibility. BLM, the BS gene product, belongs to the highly-conserved RecQ family of DNA helicases. Although the exact function of BLM in human cells remains to be defined, it seems likely that BLM eliminates some form of homologous recombination (HR) intermediate that arises during DNA replication. Similarly, the mismatch repair (MMR) system also plays a crucial role in the maintenance of genomic stability, by correcting DNA errors generated during DNA replication. Recent evidence implicates components of the MMR system also in HR repair. We now show that hMSH6, a component of the heterodimeric mismatch recognition complex hMSH2/hMSH6 (hMutS(alpha)), interacts with the BLM protein both in vivo and in vitro. In agreement with these findings, BLM and hMSH6 co-localise to discrete nuclear foci following exposure of the cells to ionising radiation. However, the purified recombinant MutS(alpha) complex does not affect the helicase activity of BLM in vitro. As BLM has previously been shown to interact with the hMLH1 component of the hMLH1/hPMS2 (hMutL(alpha)) heterodimeric MMR complex, our present findings further strengthen the link between BLM and processes involving correction of DNA mismatches, such as in the regulation of the fidelity of homologous recombination events.

Bloom's syndrome (BS) is a rare genetic disorder characterised by genome instability and cancer susceptibility. BLM, the BS gene product, belongs to the highly-conserved RecQ family of DNA helicases. Although the exact function of BLM in human cells remains to be defined, it seems likely that BLM eliminates some form of homologous recombination (HR) intermediate that arises during DNA replication. Similarly, the mismatch repair (MMR) system also plays a crucial role in the maintenance of genomic stability, by correcting DNA errors generated during DNA replication. Recent evidence implicates components of the MMR system also in HR repair. We now show that hMSH6, a component of the heterodimeric mismatch recognition complex hMSH2/hMSH6 (hMutS(alpha)), interacts with the BLM protein both in vivo and in vitro. In agreement with these findings, BLM and hMSH6 co-localise to discrete nuclear foci following exposure of the cells to ionising radiation. However, the purified recombinant MutS(alpha) complex does not affect the helicase activity of BLM in vitro. As BLM has previously been shown to interact with the hMLH1 component of the hMLH1/hPMS2 (hMutL(alpha)) heterodimeric MMR complex, our present findings further strengthen the link between BLM and processes involving correction of DNA mismatches, such as in the regulation of the fidelity of homologous recombination events.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Molecular Cancer Research
07 Faculty of Science > Institute of Molecular Cancer Research
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:2003
Deposited On:09 Jul 2010 07:18
Last Modified:05 Apr 2016 13:57
Publisher:De Gruyter
ISSN:1431-6730
Publisher DOI:https://doi.org/10.1515/BC.2003.128
PubMed ID:12974384
Permanent URL: https://doi.org/10.5167/uzh-31240

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