The Genome Stability Maintenance DNA Helicase DDX11 and Its Role in Cancer.

DDX11/ChlR1 is a super-family two iron-sulfur cluster containing DNA helicase with roles in DNA replication and sister chromatid cohesion establishment, and general chromosome architecture. Bi-allelic mutations of the DDX11 gene cause a rare hereditary disease, named Warsaw breakage syndrome, characterized by a complex spectrum of clinical manifestations (pre- and post-natal growth defects, microcephaly, intellectual disability, heart anomalies and sister chromatid cohesion loss at cellular level) in accordance with the multifaceted, not yet fully understood, physiological functions of this DNA helicase. In the last few years, a possible role of DDX11 in the onset and progression of many cancers is emerging. Herein we summarize the results of recent studies, carried out either in tumoral cell lines or in xenograft cancer mouse models, suggesting that DDX11 may have an oncogenic role. The potential of DDX11 DNA helicase as a pharmacological target for novel anti-cancer therapeutic interventions, as inferred from these latest developments, is also discussed.

Functional Coupling between DNA Replication and Sister Chromatid Cohesion Establishment.

Several lines of evidence suggest the existence in the eukaryotic cells of a tight, yet largely unexplored, connection between DNA replication and sister chromatid cohesion. Tethering of newly duplicated chromatids is mediated by cohesin, an evolutionarily conserved hetero-tetrameric protein complex that has a ring-like structure and is believed to encircle DNA. Cohesin is loaded onto chromatin in telophase/G1 and converted into a cohesive state during the subsequent S phase, a process known as cohesion establishment. Many studies have revealed that down-regulation of a number of DNA replication factors gives rise to chromosomal cohesion defects, suggesting that they play critical roles in cohesion establishment. Conversely, loss of cohesin subunits (and/or regulators) has been found to alter DNA replication fork dynamics. A critical step of the cohesion establishment process consists in cohesin acetylation, a modification accomplished by dedicated acetyltransferases that operate at the replication forks. Defects in cohesion establishment give rise to chromosome mis-segregation and aneuploidy, phenotypes frequently observed in pre-cancerous and cancerous cells. Herein, we will review our present knowledge of the molecular mechanisms underlying the functional link between DNA replication and cohesion establishment, a phenomenon that is unique to the eukaryotic organisms.

Role of the DDX11 DNA Helicase in Warsaw Breakage Syndrome Etiology.

Warsaw breakage syndrome (WABS) is a genetic disorder characterized by sister chromatid cohesion defects, growth retardation, microcephaly, hearing loss and other variable clinical manifestations. WABS is due to biallelic mutations of the gene coding for the super-family 2 DNA helicase DDX11/ChlR1, orthologous to the yeast chromosome loss protein 1 (Chl1). WABS is classified in the group of "cohesinopathies", rare hereditary diseases that are caused by mutations in genes coding for subunits of the cohesin complex or protein factors having regulatory roles in the sister chromatid cohesion process. In fact, among the cohesion regulators, an important player is DDX11, which is believed to be important for the functional coupling of DNA synthesis and cohesion establishment at the replication forks. Here, we will review what is known about the molecular and cellular functions of human DDX11 and its role in WABS etiopathogenesis, even in light of recent findings on the role of cohesin and its regulator network in promoting chromatin loop formation and regulating chromatin spatial organization.

Warsaw Breakage Syndrome associated DDX11 helicase resolves G-quadruplex structures to support sister chromatid cohesion.

Warsaw Breakage Syndrome (WABS) is a rare disorder related to cohesinopathies and Fanconi anemia, caused by bi-allelic mutations in DDX11. Here, we report multiple compound heterozygous WABS cases, each displaying destabilized DDX11 protein and residual DDX11 function at the cellular level. Patient-derived cell lines exhibit sensitivity to topoisomerase and PARP inhibitors, defective sister chromatid cohesion and reduced DNA replication fork speed. Deleting DDX11 in RPE1-TERT cells inhibits proliferation and survival in a TP53-dependent manner and causes chromosome breaks and cohesion defects, independent of the expressed pseudogene DDX12p. Importantly, G-quadruplex (G4) stabilizing compounds induce chromosome breaks and cohesion defects which are strongly aggravated by inactivation of DDX11 but not FANCJ. The DNA helicase domain of DDX11 is essential for sister chromatid cohesion and resistance to G4 stabilizers. We propose that DDX11 is a DNA helicase protecting against G4 induced double-stranded breaks and concomitant loss of cohesion, possibly at DNA replication forks.

Influence of chronic neck pain on cervical joint position error (JPE): Comparison between young and elderly subjects.

BACKGROUND: Evaluation of cervical joint position sense in subjects with chronic neck pain has gained importance in recent times. Different authors have established increased joint position error (JPE) in subjects with acute neck pain. However, there is a paucity of studies to establish the influence of chronic neck pain on cervical JPE. OBJECTIVE: The objective of the study was to understand the influence of chronic neck pain on cervical JPE, and to examine the differences in cervical JPE between young and elderly subjects with chronic neck pain. METHODS: Forty-two chronic neck pain patients (mean age 47.4) were compared for cervical JPE with 42 age-matched healthy subjects (mean age 47.8), using a digital inclinometer. The cervical JPE were measured in flexion, extension, and rotation in right and left movement directions. RESULTS: The comparison of JPE showed significantly larger errors in subjects with chronic neck pain when compared to healthy subjects (p< 0.001). The errors were larger in all of the movement directions tested. Comparison between young and older subjects with chronic neck pain revealed no significant differences (P> 0.05) in cervical JPE. CONCLUSIONS: Cervical joint position sense is impaired in subjects with chronic neck pain.

Intra- and inter-rater reliability of neutral head position and target head position tests in patients with and without neck pain.

BACKGROUND: Cervical proprioception is a common term used in neck rehabilitation, and it is examined using neutral head position (NHP) and target head position (THP) tests. OBJECTIVE: To investigate intra- and inter-rater reliability of the NHP and THP tests in patients with neck pain and in healthy controls. METHODS: The intra-rater (between-day) and inter-rater (within-day) reliability of the NHP and THP tests were assessed in 36 patients with neck pain and 33 healthy subjects. NHP testing was evaluated in cervical extension, while THP testing was evaluated in six directions of cervical motion: cervical flexion, extension, side bending right, side bending left, rotation right, and rotation left. RESULTS: The intra-rater reliability for the NHP tests had intraclass correlation coefficient (ICC) values of 0.74-0.78 and a standard error of measurement (SEM) of 1.78-1.88; the THP tests had ICC values of 0.70-0.83 and SEM of 1.45-2.45. Likewise, inter-rater reliability for NHP had ICC values of 0.74-0.79 and SEM of 1.79-1.87. For the THP test, the inter-rater reliability had ICC values of 0.62-0.84 and SEM of 1.50-2.23. CONCLUSION: Intra- and inter-rater reliability ranged from good to very good agreement both for NHP and for THP tests of cervical proprioception.