Molecular and cellular functions of the FANCJ DNA helicase defective in cancer and in Fanconi anemia

Abstract

The FANCJ DNA helicase is mutated in hereditary breast and ovarian cancer as well as the progressive bone marrow failure disorder Fanconi anemia (FA). FANCJ is linked to cancer suppression and DNA double strand break repair through its direct interaction with the hereditary breast cancer associated gene product, BRCA1. FANCJ also operates in the FA pathway of interstrand cross-link repair and contributes to homologous recombination. FANCJ collaborates with a number of DNA metabolizing proteins implicated in DNA damage detection and repair, and plays an important role in cell cycle checkpoint control. In addition to its role in the classical FA pathway, FANCJ is believed to have other functions that are centered on alleviating replication stress. FANCJ resolves G-quadruplex (G4) DNA structures that are known to affect cellular replication and transcription, and potentially play a role in the preservation and functionality of chromosomal structures such as telomeres. Recent studies suggest that FANCJ helps to maintain chromatin structure and preserve epigenetic stability by facilitating smooth progression of the replication fork when it encounters DNA damage or an alternate DNA structure such as a G4. Ongoing studies suggest a prominent but still not well-understood role of FANCJ in transcriptional regulation, chromosomal structure and function, and DNA damage repair to maintain genomic stability. This review will synthesize our current understanding of the molecular and cellular functions of FANCJ that are critical for chromosomal integrity.

Close encounters for the first time: Helicase interactions with DNA damage

“…More recently, we observed that the Fanconi Anemia Group J helicase (FANCJ, also called BACH1 or BRIP1) that is genetically implicated in Fanconi Anemia (FA) as well as breast and ovarian cancer [12,13] is inhibited by a polyglycol modification positioned in the 5′ single-stranded tail, but not the 3′ single-stranded tail, when it is located immediately adjacent to the duplex region of the forked helicase substrate [14]. This finding is consistent with the known 5′ to 3′ directionality of FANCJ translocation on single-stranded DNA [15]. …”

FANCJ suppresses microsatellite instability and lymphomagenesis independent of the Fanconi anemia pathway

“…Importantly, of the microsatellites that are unstable in Fancj −/− MEFs, CAG/CTG, TTC/GAA, CA/TG, and CT/AG repeats are potential DNA slippage sites, and CAG/CTG, TTC/GAA, CT/ AG, and CA/TG are believed to form hairpin-like structures, triplex structures, triplex structures, and Z-DNA structures, respectively (Zhao et al 2010). Since FANCJ has been shown to unwind a variety of DNA secondary structures in vitro (Brosh and Cantor 2014), including, but not limited to, hairpins and triplex structures, we propose that FANCJ acts to suppress MSI by dismantling DNA secondary structures that favor repeat sequence expansion or contraction via a strand slippage mechanism (Fig. 7E), which is distinct from error correction by MMR.…”

“…One of the most enigmatic FA proteins is FANCJ, a DEAH superfamily 2 helicase and part of the subfamily of Fe-S cluster-containing helicases, which also includes XPD, RTEL1, and CHL1 (Rudolf et al 2006;Gari et al 2012;Brosh and Cantor 2014). Biallelic mutations in FANCJ give rise to FA complementation group J (Levitus et al 2005;Levran et al 2005;Litman et al 2005), whereas monoallelic mutations predispose to ovarian and breast cancers (Seal et al 2006;Rafnar et al 2011).…”

Genetic Profile Analysis of a Patient with Metachronous Gastric Cancer with a Family History of Gastrointestinal Cancers

“…Fanconi anemia is a rare autosomal recessive disorder associated with progressive bone marrow failure, skeletal abnormality and cancer. 16 There was no literature of review or case report about the relationship between BRIP1…”