Article
- The EMBO Journal (2007) 26, 3238 - 3249
- doi:10.1038/sj.emboj.7601754
Published online: 21 June 2007
Subject Category:
The FANCJ/MutL
interaction is required for correction of the cross-link response in FA-J cells
Min Peng1,a, Rachel Litman1,a, Jenny Xie1, Sudha Sharma2, Robert M Brosh Jr2 and Sharon B Cantor1
- Department of Cancer Biology, University of Massachusetts Medical School Women's Cancers Program, UMASS Memorial Cancer Center, Worcester, MA, USA
- Laboratory of Molecular Gerontology, National Institute on Aging, NIH, Baltimore, MD, USA
Correspondence to:
Sharon B Cantor, Department of Cancer Biology, UMASS Medical School, 364 Plantation Street, LRB 415, Worcester, MA 01605, USA. Tel.: +1 508 856 4421; Fax: +1 508 856 1310; E-mail: Sharon.Cantor@umassmed.edu
aThese authors contributed equally to this work
Received 14 May 2007; Accepted 16 May 2007
Abstract
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 MutL
, 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/MutL interaction, but not FANCJ/BRCA1 interaction, is essential for establishment of a normal ICL-induced response. The functional role of the FANCJ/MutL complex demonstrates a novel link between FA and MMR, and predicts a broader role for FANCJ in DNA damage signaling independent of BRCA1.
Keywords:
- BRIP1/BACH1,
- FANCJ,
- Fanconi anemia,
- interstrand crosslinks,
- mismatch repair,
- MutL (MLH1/PMS2)
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated
REVIEWS
Mechanisms and functions of DNA mismatch repair
Cell Research Review
Emergence of a DNA-damage response network consisting of Fanconi anaemia and BRCA proteins
Nature Reviews Genetics Review (01 Oct 2007)
NEWS AND VIEWS
A major switch for the Fanconi anemia DNA damage?response pathway
Nature Structural & Molecular Biology News and Views (01 Nov 2008)
RESEARCH
FAAP100 is essential for activation of the Fanconi anemia-associated DNA damage response pathway
The EMBO Journal Article (18 Apr 2007)
A novel protein, MAPO1, that functions in apoptosis triggered by O 6 -methylguanine mispair in DNA
Oncogene Original Article
