Editors' ChoiceCancer

SNFing Out Vulnerability in Cancer

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Science Translational Medicine  21 May 2014:
Vol. 6, Issue 237, pp. 237ec88
DOI: 10.1126/scitranslmed.3009311

Originally discovered in yeast but conserved in eukaryotes, the SWI/SWF complex is a group of proteins that remodel the packaging of DNA (the chromatin) to regulate transcription. Aside from its role in transcriptional regulation, chromatin remodeling was recently found also to be involved in the repair of DNA damage by allowing the DNA repair proteins access to damaged regions of the DNA. Watanabe et al. embarked on a set of experiments to understand the role of SWI/SNF proteins in the DNA damage response. First, they investigated the role of the ARID1A and ARID1B genes, which are frequently mutated in human cancers, in nonhomologous end-joining repair (NHEJ). They found that in lung cancer cell lines, ARID1A and ARID1B localize to DNA damage sites. When the researchers used small interfering RNA to suppress either gene, the result was reduced NHEJ, suggesting that both genes were required for full NHEJ activity. They also found that the recruitment of the green fluorescent protein–tagged DNA repair proteins KU70, KU80, and subsequently XRCC to the site of DNA double-strand breaks was impaired when either ARID1A or ARID1B were inhibited. Similar experiments suggested that several other proteins of the SWI/SWF complex were also necessary for fully functional NHEJ. Watanabe et al. demonstrated that the stability of several proteins in the SWI/SNF complex was interdependent, indicating that the loss of one SWI/SWF protein may lead to the instability of other proteins in the same complex.

The investigators also found that the suppression of ARID1A, ARID1B, or any of several other members of the SWI/SWF complex sensitized cancer cells to cisplatin, a commonly used chemotherapeutic drug that induces DNA damage through intra- and interstrand DNA cross-links. This paper demonstrates that both ARID1 proteins are required for NHEJ and that cancer cells lacking these proteins or other SWI/SNF factors are more sensitive to DNA-damaging chemotherapeutic agents such as cisplatin. Because these genes are frequently mutated in cancers, it is an important vulnerability that could be exploited therapeutically.

R. Watanabe et al., SWI/SNF factors required for cellular resistance to DNA damage include ARID1A and ARID1B and show interdependent protein stability. Cancer Res. 74, 2465–2475 (2014). [Abstract]

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