Hereditary breast cancer and the BRCA1-associated FANCJ/BACH1/BRIP1

Abstract

It is clear that FANCJ, also known as BACH1 or BRIP1, is an essential tumor suppressor gene based on the identification of clinically relevant mutations not only in breast cancer, but also the childhood cancer syndrome, Fanconi anemia. This conclusion is further supported by the direct and functional interaction between FANCJ and the hereditary breast cancer-associated gene product BRCA1. In the absence of the FANCJ DNA helicase or its interaction with BRCA1, cells have defects in several aspects of the DNA damage response. In particular, the BRCA1-FANCJ interaction is essential for promoting error-free repair, checkpoint control and for limiting DNA damage tolerance. As the number of FANCJ clinical mutations and affected patients accumulate, it will be critical to understand whether the associated tumors resemble BRCA-associated tumors. If so, FANCJ patients could also benefit from new therapies that selectively sensitize DNA repair-defective tumors and spare healthy cells. In this article, we summarize the breast cancer-associated FANCJ mutations and discuss functional outcomes for DNA repair and tumor suppression.

Figure 1. DNA repair genes associated with hereditary breast cancer and linked to Fanconi anemia

Genetic susceptibility to breast cancer is attributed to germline mutations in either BRCA1 or BRCA2 as well as other genes, notably some genes that encode for BRCA1- and BRCA2-interacting proteins, FANCJ and PALB2. The percentage of contribution of the non-BRCA genes is unclear and not indicated. Inheriting bi-allelic mutations in some breast cancer genes, which are underlined, results in Fanconi anemia associated with complementation groups BRCA2/FANCD1, PALB2/FANCN and BACH1/FANCJ/BRIP1.

Figure 2. FANCJ mutation sites and functional domains

Shown are some FANCJ clinically relevant germline mutations: breast cancer mutations (pink), Fanconi anemia mutations (blue; see [101]) one mutation shared by both diseases is shown (pink/blue). In addition, the 7-helicase blocks are depicted, with noted DEAH residues, Fe–S domain, NLS, the K52R mutation that inactivates its enzyme activity and phosphorylation on serine 990 that is required for binding to BRCA1. Fe–S: Iron–sulfur; NLS: Nuclear localization sequence.

Figure 3. FANCJ tumor suppression function

FANCJ tumor suppression and DNA repair functions require the ability to interact with BRCA1 for its enzyme activity to be regulated. Too little (loss of function) or too much enzyme activity and/or loss of BRCA1 binding (gain of function) will promote tumorigenesis.