It was reported that DDX11-depleted U2OS cells were resistant to treatment with Telomestatin, a G4 DNA-binder, and did not display increased DNA damage (using γ-H2AX foci formation as a readout) upon treatment with this compound. 10 Nonetheless, the physiological relevance of DDX11 substrate preference is not completely understood. 7 A similar protein displacement activity was also demonstrated for the Fe–S DNA helicase FANCJ, whereas human RECQ1, Werner and Bloom DNA helicases do not display this enzymatic function. Besides, DDX11 was proposed to displace proteins bound to DNA, as it was found to be able to disrupt the high-affinity streptavidin:biotin interaction in a helicase protein concentration- and ATP-dependent manner in assays where biotinylated oligonucleotides bound to streptavidin were used as substrates. In contrast, unimolecular G4- and Holliday junction-containing DNA molecules are not resolved by DDX11. Additional substrates of the DDX11 helicase are three-stranded D-loops with an invading 3ʹ-end, bi-molecular anti-parallel G-quadruplex (G4) with two 5ʹ-tails and DNA molecules containing triple-stranded (triplex) structures with a 5ʹ-single-stranded overhang on the third strand. 1, 2, 5– 9 DDX11 DNA helicase was reported to preferentially unwinds forked duplex DNA substrates with non-complementary 5ʹ- and 3ʹ-single-stranded arms whereas, DNA molecules having blunt ends or only a 3ʹ-tail are not unwound by DDX11 in enzymatic assays carried out in vitro. The biochemical and enzymatic properties of human DDX11 were investigated in many laboratories in the last two decades. 2 Molecular Properties and Cellular Functions of DDX11 Here, I review what is known about WABS in terms of clinical reports, diagnostic tools, disease animal model systems and ethiopathogenesis in light of the most recent discoveries of DDX11 physiological roles. This latter also includes the Xeroderma pigmentosum group D (XPD) protein, FANCJ and RTEL1, which all have key roles in genome maintenance pathways and are linked to rare genetic syndromes and cancer predisposition. The presence of an iron–sulfur cluster (Fe–S) domain classifies DDX11 as a member of the subgroup of Fe–S DNA helicases. DDX11 (also named ChlR1, being related to the Saccharomyces cerevisiae chromosome loss 1, Chl1, protein) is an ATP-dependent DNA helicase with 5′ to 3′ directionality that belongs to the DNA helicase super-family 2 (SF2). 1, 2 Cardinal clinical features observed in WABS patients include severe pre- and post-natal growth retardation, microcephaly, sensorineural hearing loss, cochlear anomalies, facial dysmorphia and sister chromatid cohesion defects. Warsaw breakage syndrome (WABS) is a very rare autosomal recessive disease due to bi-allelic mutations of the gene coding for the DNA helicase DDX11. Keywords: cohesinopathies, developmental disorders, Warsaw breakage syndrome, DDX11, genome stability, sister chromatid cohesion Ethiopathogenesis of WABS is discussed in line with these recent findings and evidence of a possible role of DDX11 as a cohesin regulator. This “non-canonical” function of cohesin is expected to impact gene transcription during cell differentiation and embryonic development and its dis-regulation, caused by mutation/loss of genes encoding cohesin subunits or regulators, could originate the developmental defects observed in cohesinopathies. Recent evidences suggest that cohesin and its regulators have additional key roles in chromatin organization by promoting the formation of chromatin loops. However, WABS is considered to belong to the group of cohesinopathies, genetic disorders due to mutations of subunits or regulators of cohesin, the protein complex responsible for tethering sister chromatids from the time of their synthesis till they separate in mitosis. Molecular bases of WABS have not yet been elucidated, due to lack of disease animal model systems and limited knowledge of the DDX11 physiological functions. Typical clinical features observed in WABS patients include growth retardation, facial dysmorphia, microcephaly, hearing loss due to cochlear malformations and, at cytological level, sister chromatid cohesion defects. Castellino, 111, Naples, ItalyĪbstract: Warsaw breakage syndrome (WABS) is a very rare recessive hereditary disease caused by mutations in the gene coding for the DNA helicase DDX11, involved in genome stability maintenance and sister cohesion establishment. Istituto di Biochimica e Biologia Cellulare, Consiglio Nazionale delle Ricerche, Via P.

Istituto di Biochimica e Biologia Cellulare, Consiglio Nazionale delle Ricerche, Naples 80131, Italy

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