scholarly journals Molecular and Cellular Functions of the Warsaw Breakage Syndrome DNA Helicase DDX11

Genes ◽  
2018 ◽  
Vol 9 (11) ◽  
pp. 564 ◽  
Author(s):  
Francesca Pisani ◽  
Ettore Napolitano ◽  
Luisa Napolitano ◽  
Silvia Onesti
Keyword(s):  
Sister Chromatid ◽  
Genome Stability ◽  
Genetic Disorder ◽  
Structural Features ◽  
Dna Helicase ◽  
Sister Chromatid Cohesion ◽  
Cellular Functions ◽  
Dna Helicases ◽  
Multiple Protein ◽  
Chromatid Cohesion

DDX11/ChlR1 (Chl1 in yeast) is a DNA helicase involved in sister chromatid cohesion and in DNA repair pathways. The protein belongs to the family of the iron–sulphur cluster containing DNA helicases, whose deficiencies have been linked to a number of diseases affecting genome stability. Mutations of human DDX11 are indeed associated with the rare genetic disorder named Warsaw breakage syndrome, showing both chromosomal breakages and chromatid cohesion defects. Moreover, growing evidence of a potential role in oncogenesis further emphasizes the clinical relevance of DDX11. Here, we illustrate the biochemical and structural features of DDX11 and how it cooperates with multiple protein partners in the cell, acting at the interface of DNA replication/repair/recombination and sister chromatid cohesion to preserve genome stability.

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

Genes ◽  
2021 ◽  
Vol 12 (3) ◽  
pp. 395
Author(s):  
Mohammad Mahtab ◽  
Ana Boavida ◽  
Diana Santos ◽  
Francesca M. Pisani
Keyword(s):  
Sister Chromatid ◽  
Genome Stability ◽  
Clinical Manifestations ◽  
Hereditary Disease ◽  
Dna Helicase ◽  
Sister Chromatid Cohesion ◽  
Cellular Level ◽  
Therapeutic Interventions ◽  
Complex Spectrum ◽  
Chromatid Cohesion

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.

scholarly journals Role of the DDX11 DNA Helicase in Warsaw Breakage Syndrome Etiology

2021 ◽  
Vol 22 (5) ◽  
pp. 2308
Author(s):  
Diana Santos ◽  
Mohammad Mahtab ◽  
Ana Boavida ◽  
Francesca M. Pisani
Keyword(s):  
Sister Chromatid ◽  
Genetic Disorder ◽  
Clinical Manifestations ◽  
Dna Helicase ◽  
Sister Chromatid Cohesion ◽  
Functional Coupling ◽  
Chromosome Loss ◽  
Loop Formation ◽  
Chromatid Cohesion

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.

scholarly journals Interaction of the Warsaw breakage syndrome DNA helicase DDX11 with the replication fork-protection factor Timeless promotes sister chromatid cohesion

PLoS Genetics ◽  
2018 ◽  
Vol 14 (10) ◽  
pp. e1007622 ◽  
Author(s):  
Giuseppe Cortone ◽  
Ge Zheng ◽  
Pasquale Pensieri ◽  
Viviana Chiappetta ◽  
Rosarita Tatè ◽  
...  
Keyword(s):  
Sister Chromatid ◽  
Replication Fork ◽  
Dna Helicase ◽  
Sister Chromatid Cohesion ◽  
Protection Factor ◽  
Chromatid Cohesion

Sister chromatid cohesion and genome stability in vertebrate cells

2003 ◽  
Vol 31 (1) ◽  
pp. 263-265 ◽  
Author(s):  
C. Morrison ◽  
P. Vagnarelli ◽  
E. Sonoda ◽  
S. Takeda ◽  
W.C. Earnshaw
Keyword(s):  
Dna Repair ◽  
Chromosome Segregation ◽  
Sister Chromatid ◽  
Genome Stability ◽  
Sister Chromatid Cohesion ◽  
Spindle Poles ◽  
Chromatid Cohesion ◽  
Chromosomal Passenger ◽  
Passenger Protein

For successful eukaryotic mitosis, sister chromatid pairs remain linked after replication until their kinetochores have been attached to opposite spindle poles by microtubules. This linkage is broken at the metaphase–anaphase transition and the sisters separate. In budding yeast, this sister chromatid cohesion requires a multi-protein complex called cohesin. A key component of cohesin is Scc1/Mcd1 (Rad21 in fission yeast). Disruption of the chicken orthologue of Scc1 by gene targeting in DT40 cells causes premature sister chromatid separation. Cohesion between sister chromatids is likely to provide a substrate for post-replicative DNA repair by homologous recombination. In keeping with this role of cohesion, Scc1 mutants also show defects in the repair of spontaneous and induced DNA damage. Scc1-deficient cells frequently fail to complete metaphase chromosome alignment and show chromosome segregation defects, suggesting aberrant kinetochore function. Consistent with this, the chromosomal passenger protein, INCENP (inner centromere protein) fails to localize to centromeres. Survivin, another passenger protein and one which interacts with INCENP, also fails to localize to centromeres in Scc1-deficient cells. These results show that cohesin maintains genomic stability by ensuring appropriate DNA repair and equal chromosome segregation at mitosis.

scholarly journals Mrc1 Is Required for Sister Chromatid Cohesion To Aid in Recombination Repair of Spontaneous Damage

2004 ◽  
Vol 24 (16) ◽  
pp. 7082-7090 ◽  
Author(s):  
Hong Xu ◽  
Charles Boone ◽  
Hannah L. Klein
Keyword(s):  
Dna Damage ◽  
Dna Replication ◽  
Homologous Recombination ◽  
Sister Chromatid ◽  
Synthetic Lethality ◽  
Dna Helicase ◽  
Sister Chromatid Cohesion ◽  
Checkpoint Response ◽  
Chromatid Cohesion

ABSTRACT The SRS2 gene of Saccharomyces cerevisiae encoding a 3′→5′ DNA helicase is part of the postreplication repair pathway and functions to ensure proper repair of DNA damage arising during DNA replication through pathways that do not involve homologous recombination. Through a synthetic gene array analysis, genes that are essential when Srs2 is absent have been identified. Among these are MRC1, TOF1, and CSM3, which mediate the intra-S checkpoint response. srs2Δ mrc1Δ synthetic lethality is due to inappropriate recombination, as the lethality can be suppressed by genetic elimination of homologous recombination. srs2Δ mrc1Δ synthetic lethality is dependent on the role of Mrc1 in DNA replication but independent of the role of Mrc1 in a DNA damage checkpoint response. mrc1Δ, tof1Δ and csm3Δ mutants have sister chromatid cohesion defects, implicating sister chromatid cohesion established at the replication fork as an important factor in promoting repair of stalled replication forks through gap repair.

scholarly journals The DNA helicase ChlR1 is required for sister chromatid cohesion in mammalian cells

2006 ◽  
Vol 119 (23) ◽  
pp. 4857-4865 ◽  
Author(s):  
J. L. Parish ◽  
J. Rosa ◽  
X. Wang ◽  
J. M. Lahti ◽  
S. J. Doxsey ◽  
...  
Keyword(s):  
Sister Chromatid ◽  
Mammalian Cells ◽  
Dna Helicase ◽  
Sister Chromatid Cohesion ◽  
Chromatid Cohesion

scholarly journals Rpd3L and Hda1 histone deacetylases facilitate repair of broken forks by promoting sister chromatid cohesion

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Pedro Ortega ◽  
Belén Gómez-González ◽  
Andrés Aguilera
Keyword(s):  
Sister Chromatid ◽  
Histone Deacetylases ◽  
Genome Stability ◽  
Genome Instability ◽  
Sister Chromatid Cohesion ◽  
Histone Deacetylation ◽  
Strand Breaks ◽  
Chromatid Cohesion ◽  
Dna Strands

AbstractGenome stability involves accurate replication and DNA repair. Broken replication forks, such as those encountering a nick, lead to double strand breaks (DSBs), which are preferentially repaired by sister-chromatid recombination (SCR). To decipher the role of chromatin in eukaryotic DSB repair, here we analyze a collection of yeast chromatin-modifying mutants using a previously developed system for the molecular analysis of repair of replication-born DSBs by SCR based on a mini-HO site. We confirm the candidates through FLP-based systems based on a mutated version of the FLP flipase that causes nicks on either the leading or lagging DNA strands. We demonstrate that Rpd3L and Hda1 histone deacetylase (HDAC) complexes contribute to the repair of replication-born DSBs by facilitating cohesin loading, with no effect on other types of homology-dependent repair, thus preventing genome instability. We conclude that histone deacetylation favors general sister chromatid cohesion as a necessary step in SCR.

scholarly journals New Functions of Ctf18-RFC in Preserving Genome Stability outside Its Role in Sister Chromatid Cohesion

PLoS Genetics ◽  
2011 ◽  
Vol 7 (2) ◽  
pp. e1001298 ◽  
Author(s):  
Lionel Gellon ◽  
David F. Razidlo ◽  
Olive Gleeson ◽  
Lauren Verra ◽  
Danae Schulz ◽  
...  
Keyword(s):  
Sister Chromatid ◽  
Genome Stability ◽  
Sister Chromatid Cohesion ◽  
Chromatid Cohesion
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