Goat anti-Human BACH1.3 polyclonal antibody

FANCJ mutations are associated with breast cancer and genetically linked to the bone marrow disease Fanconi anemia (FA). The genomic instability of FA-J mutant cells suggests that FANCJ helicase functions in the replicational stress response. A putative helicase with sequence similarity to FANCJ in Caenorhabditis elegans (DOG-1) and mouse (RTEL) is required for poly(G) tract maintenance, suggesting its involvement in the resolution of alternate DNA structures that impede replication. Under physiological conditions, guanine-rich sequences spontaneously assemble into four-stranded structures (G quadruplexes [G4]) that influence genomic stability. FANCJ unwound G4 DNA substrates in an ATPase-dependent manner. FANCJ G4 unwinding is specific since another superfamily 2 helicase, RECQ1, failed to unwind all G4 substrates tested under conditions in which the helicase unwound duplex DNA. Replication protein A stimulated FANCJ G4 unwinding, whereas the mismatch repair complex MSH2/MSH6 inhibited this activity. FANCJ-depleted cells treated with the G4-interactive compound telomestatin displayed impaired proliferation and elevated levels of apoptosis and DNA damage compared to small interfering RNA control cells, suggesting that G4 DNA is a physiological substrate of FANCJ. Although the FA pathway has been classically described in terms of interstrand cross-link (ICL) repair, the cellular defects associated with FANCJ mutation extend beyond the reduced ability to repair ICLs and involve other types of DNA structural roadblocks to replication.

The Keap1-Nrf2 signal transduction pathway plays a major role in oxidant and electrophile induction of adaptive homeostasis that transiently and reversibly increases cellular and organismal protection from stress. By expanding (and then contracting) the normal homeostatic range of expression of stress-protective genes, Nrf2 allows us to cope with fluctuations in stress levels. Two major inhibitors of Nrf2 are Bach1 and c-Myc which normally serve the important function of turning off adaptation when appropriate. We have found, however, that both Bach1 and c-Myc levels increase substantially with age and that older human cells, worms, flies, and mice loose Nrf2-dependent signaling and adaptive homeostasis. Nrf2 has also been linked with increased risk of cancers, and cancer incidence certainly increases with age. Here we propose that the age-dependent increase in Bach1 and c-Myc may actually cause the age-dependent decline in Nrf2 signaling and adaptive homeostasis, and that this is a coordinated attempt to minimize the age-dependent increase in cancer incidence. In other words, we may trade off adaptive homeostasis for a lower risk of cancer by increasing Bach1 and c-Myc in ageing.