The FANCJ/MutLa interaction is required for correction of the cross-link response in FA-J cells

Department of Cancer Biology, University of Massachusetts Medical School Women's Cancers Program, UMASS Memorial Cancer Center, Worcester, MA, USA.
The EMBO Journal (Impact Factor: 10.43). 08/2007; 26(13):3238-49. DOI: 10.1038/sj.emboj.7601754
Source: PubMed


FANCJ also called BACH1/BRIP1 was first linked to hereditary breast cancer through its direct interaction with BRCA1. FANCJ was also recently identified as a Fanconi anemia (FA) gene product, establishing FANCJ as an essential tumor suppressor. Similar to other FA cells, FANCJ-null (FA-J) cells accumulate 4N DNA content in response to DNA interstrand crosslinks (ICLs). This accumulation is corrected by reintroduction of wild-type FANCJ. Here, we show that FANCJ interacts with the mismatch repair complex MutLalpha, composed of PMS2 and MLH1. Specifically, FANCJ directly interacts with MLH1 independent of BRCA1, through its helicase domain. Genetic studies reveal that FANCJ helicase activity and MLH1 binding, but not BRCA1 binding, are essential to correct the FA-J cells' ICL-induced 4N DNA accumulation and sensitivity to ICLs. These results suggest that the FANCJ/MutLalpha interaction, but not FANCJ/BRCA1 interaction, is essential for establishment of a normal ICL-induced response. The functional role of the FANCJ/MutLalpha complex demonstrates a novel link between FA and MMR, and predicts a broader role for FANCJ in DNA damage signaling independent of BRCA1.

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Available from: Sudha Sharma, Dec 30, 2013
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    • "Beyond HR, BRIP1 also contributes to processing interstrand crosslinks (ICLs) during MMR [21] [46]. This is mediated, in a BRCA1 independent manner, through its interaction with the MutLα mismatch repair complex, consisting of the MLH1 and PMS2 heterodimer [60] [61]. Upon mismatch Fig. 1. "
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    • ", and pOZ vectors and stable FA-J cell lines was described (Peng et al, 2007). Stable shRNA cells were selected with puromycin. "
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    • "Nuclear extracts were incubated with anti-MLH1, or anti-GFP control Abs, and then examined for co-IP partners by Western. First, we tested for the integrity of the MLH1:PMS2 complex [21] and the capability of MLH1 to interact with MBD4. IP with anti-MLH1 pulls down MLH1 and PMS2, as well as MBD4 (fig. "
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