DDX11

DDX11 Full Name

DEAD/H (Asp-Glu-Ala-Asp/His) box helicase 11

DDX11 Introduction

DDX11 encodes an ATP-dependent DNA helicase, also known as ChlR1, that is essential for the accurate duplication and segregation of the genome. DDX11 belongs to the DEAD/H-box family of helicases, but unlike the many family members that act on RNA, DDX11 unwinds double-stranded DNA and specializes in functions that link DNA replication to chromosome structure. Its best-characterized role is in sister chromatid cohesion, the process by which newly replicated chromosomes are held together until cell division: DDX11 facilitates the establishment of cohesion during replication, ensuring that the two sister chromatids remain physically linked so that they can be segregated correctly into daughter cells. The helicase also contributes to the rescue of replication forks that stall when they encounter DNA lesions or difficult-to-replicate sequences, and it participates in the repair of DNA damage that threatens genome integrity. The importance of DDX11 in humans is demonstrated by the consequences of its loss: biallelic mutations cause Warsaw breakage syndrome, a severe developmental disorder characterized by microcephaly, growth retardation, and chromosomal instability, including the sister chromatid cohesion defects and DNA breaks that give the syndrome its name. DDX11 is thus a molecular linchpin that connects the machinery of DNA replication to the mechanisms that preserve chromosome structure and prevent the genomic instability that underlies cancer and developmental disease.

Figure 1. The structure of DDX11.

Fe-S Cluster Helicase Architecture and DNA Unwinding Activity
DDX11 belongs to the iron-sulfur (Fe-S) cluster family of helicases, which also includes the Fanconi anemia protein FANCJ and the helicase RTEL1, and it contains an iron-sulfur cluster that is important for its stability and function.
The protein is built around a helicase core with conserved ATP-binding and helicase motifs, together with an N-terminal region that is characteristic of the Fe-S helicase family and a C-terminal region that mediates interactions with partner proteins.
DDX11 translocates along DNA in a 5'-to-3' direction, using the energy of ATP hydrolysis to unwind duplex DNA, and it shows specificity for structures that arise during replication, including forks and junctions.
The DDX11 gene is located on human chromosome 12, and the protein is present in the nucleus throughout the cell cycle, with activity that is particularly important during S phase when the genome is duplicated.
DDX11 interacts with components of the replication and cohesion machineries, including the cohesin loader and the replication fork protection complex, positioning it at the sites where cohesion is established.
The helicase is regulated by phosphorylation and by its recruitment to chromatin in a cell-cycle-dependent manner.
Because it unwinds specific DNA structures rather than generic duplex DNA, DDX11 acts as a specialized enzyme that resolves obstacles encountered during replication.

Sister Chromatid Cohesion, Replication Fork Stability, and Warsaw Breakage Syndrome
During DNA replication, DDX11 promotes the establishment of sister chromatid cohesion, the physical linkage between newly replicated chromatids that is essential for their faithful segregation at mitosis.
The helicase helps replication forks pass through difficult regions of the genome, such as those containing secondary structures or DNA-protein crosslinks, preventing fork collapse and the generation of DNA breaks.
Loss of DDX11 function leads to the accumulation of replication-associated DNA damage and to the premature separation of sister chromatids, hallmarks of genome instability.
Biallelic mutations in DDX11 cause Warsaw breakage syndrome, an autosomal recessive disorder whose features include microcephaly, pre- and postnatal growth retardation, abnormal skin pigmentation, and cellular phenotypes of chromosomal breakage and cohesion defects.
Cells from patients with Warsaw breakage syndrome are hypersensitive to agents that cause replication stress, confirming the role of DDX11 in protecting the replicating genome.
Because defects in DNA repair helicases predispose to cancer, and because DDX11 is required for the tolerance of replication stress, the helicase is also being studied as a potential target whose inhibition could sensitize cancer cells to chemotherapy.

Alternate Names for DDX11

DDX11; DEAD/H (Asp-Glu-Ala-Asp/His) box helicase 11; DEAD/H (Asp Glu Ala Asp/His) box polypeptide 11; DEAD/H (Asp Glu Ala Asp/His) box polypeptide 11 (S.cerevisiae CHL1 like helicase); probable ATP-dependent RNA helicase DDX11; CHL1; CHL1 like helicase homolog (S. cerevisiae); CHLR1; ChlR1; KRG2