Publication for DDX11 and TIMELESS

Species	Symbol	Function*	Entrez Gene ID*	Other ID	Gene coexpression	CoexViewer
hsa	DDX11	DEAD/H-box helicase 11	1663			[link]
hsa	TIMELESS	timeless circadian regulator	8914

Pubmed ID	Priority	Text
26503245	0.98	Tim in mammalian cells causes cohesion defects that can be partially rescued by overexpressing DDX11.
	0.97	Tim and DDX11 physically and functionally interact and act in concert to preserve replication fork progression in perturbed conditions.
	0.97	Tim- and/or DDX11-depleted cells with HU causes reduced fork rate and impaired fork restart capability.
	0.97	Tim specifically stimulates DDX11 DNA unwinding activity on a forked duplex DNA substrate
	0.97	DDX11 displacement of the radio-labeled DNA strand was increased by approximately 10-fold in the presence of Tim (Figure 1B).
	0.97	DDX11 helicase activity was measured in the presence of increasing amounts of recombinant Tim (0.15, 0.3, 0.6, 1.2, 2.4 and 4.8 pmol; lanes 4-9).
	0.97	Tim truly stimulated a DDX11 ATPase-dependent motor function, we carried out various control assays using the forked duplex DNA substrate.
	0.97	Tim and/or DDX11, were pulse-labeled with CldU for 30 min and then treated with HU for 14 h before a second labeling pulse with IdU for 60 min.
	0.97	Tim- and/or DDX11-depleted cells following HU treatment.
	0.97	Tim and DDX11 was also observed in the chromatin fraction of cell extracts by co-immuno-precipitation analysis.
	0.97	Tim with DDX11, as suggested by the fact that the two proteins establish a tight physical association either in vitro or in cells.
	0.96	DDX11 to unwind a forked 39-bp duplex DNA in the absence/presence of purified recombinant Tim.
	0.96	Tim could stimulate the DDX11 DNA unwinding activity on the forked duplex DNA substrate in a protein concentration dependent manner, as shown in Figure 1A.
	0.96	Tim had any effect on the ability of DDX11 to resolve G4 DNA structures.
	0.96	Tim or DDX11 impaired the ability of cells to rescue HU-challenged replication forks.
	0.95	Tim directly interacts with DDX11 and specifically stimulates DDX11 helicase activity on structurally distinct DNA substrates including forked duplex DNA, a three-stranded D-loop substrate and an anti-parallel bimolecular G-quadruplex (G4) DNA structure.
	0.95	Tim, but not Tipin, enhances the ATPase-dependent helicase activity of DDX11 in a dose-dependent and specific manner.
	0.95	Tim was co-pulled down with DDX11 from the chromatin fraction using anti-DDX11-specific antibodies (see Figure 5D).
	0.94	Tim enhances DDX11 binding to DNA, suggesting that the observed stimulation derives from an improved ability of DDX11 to interact with the nucleic acid substrate.
	0.94	DDX11 directly interacts with Tim.
	0.94	Tim on DDX11, we analyzed whether Tim could enhance the DNA unwinding activity of FANCJ, another Fe-S cluster SF2 DNA helicase having the same 5'-3' polarity of DDX11.
	0.94	Tim stimulates an ATPase-dependent motor function of DDX11.
	0.94	Tim or DDX11 were downregulated; whereas no additive effect was observed by co-depletion of both Tim and DDX11 (see Figure 6E and F).
	0.93	Tim stimulates DDX11 unwinding activity on forked DNA substrates up to 10-fold and on bimolecular anti-parallel G-quadruplex DNA structures and three-stranded D-loop approximately 4-5-fold.
	0.93	Tim downregulation by RNA interference in HeLa cells substantially reduces DNA replication rate in unperturbed conditions, whereas DDX11 depletion does not affect replication fork progression.
	0.93	Tim on DDX11 helicase activity is observed on structurally diverse DNA substrates that represent key intermediates of various processes implicated in genome maintenance.
	0.93	DDX11 was fluxed at increasing concentrations (from 0 to 80 nM, lower to upper curves) over a Tim-immobilized sensor-chip.
	0.92	Tim on the DNA binding ability of DDX11 was analyzed.
	0.91	Tim and DDX11-Flag, as indicated.
	0.91	Tim antibodies that were incubated with mixtures containing recombinant DDX11 and Tim proteins.
	0.91	Tim and DDX11 proteins in human cells is mutually interdependent since depletion of either one will lead to a significant reduction of its interacting partner as demonstrated by western blot analyses of whole cell extracts, a result consistent with a direct interaction between the two proteins in a cellular context.
	0.90	Tim #1 and/or DDX11 #2).
	0.89	DDX11 DNA helicase activity by Tim when ATP was omitted from the reaction mixture (see Figure 2A) or substituted with the poorly hydrolyzable analog ATP-gamma-S (see Figure 2B) in the reaction mixtures.
	0.89	DDX11 (0.15 pmol) was assayed using ATP-gamma-S instead of ATP in the absence of Tim (lane 3) or in the presence of Tim (1.1 pmol, lane 4).
	0.88	Tim and DDX11 are both required for fork progression following rescue from HU treatment (see Supplementary Figure S7).
	0.87	DDX11 and Tim (or Tipin) we assessed the effect of these checkpoint mediators on DDX11 helicase activity.
	0.87	Tim stimulates DDX11 DNA binding and ATPase activity.
	0.86	Tim without DDX11 (lane 5).
	0.84	DDX11 unwinding activity by Tim derives from an improved ability of the DNA helicase to bind and utilize the nucleic acid substrate.
	0.81	Tim and/or DDX11 depletion was carried out by an additional couple of siRNAs (see Supplementary Figure S5).
	0.81	Tim downregulation still caused shorter IdU-tract relative to control siRNAs treated cells; whereas, following HU exposure, either Tim- or DDX11-depleted cells still showed IdU-tract length reduction (see Supplementary Figure S6).
	0.79	Tim and DDX11 are epistatic in promoting efficient resumption of stalled DNA replication forks in hydroxyurea-treated cells.
	0.76	Tim (6.4 pmol) in the absence of DDX11 (lane 10).
	0.76	DDX11:DNA complex in the presence of Tim was observed for the forked duplex compared to the G4 or D-loop substrates.
	0.75	Tim and/or DDX11 depletion causes a slight reduction in Chk1 phosphorylation (less than 30% with respect to control cells, as shown in Supplementary Figure S5) in response to our mild genotoxic treatment protocol (addition of HU at 2 mM into the cell culture medium for 20 min).
	0.74	Tim and DDX11 are associated in cells, as suggested by our in vitro analysis using purified recombinant proteins.
	0.73	DDX11 helicase activity was measured in the presence of increasing amounts of recombinant Tim (0.2, 0.4, 0.8, 1.6, 3.2, 6.4 pmol; lanes 4-9).
	0.72	DDX11 with 20 fmol of radio-labeled forked duplex substrate for 30 min at 37 C. (A) The activity of DDX11 (0.15 pmol) was assayed with ATP (lanes 3 and 5) and without ATP (lanes 4 and 6) in the absence (lanes 3-4) or presence (lanes 5-6) of Tim (1.1 pmol).
	0.71	Tim did not exert any effect on FANCJ helicase activity on the same forked duplex DNA substrate that was used for the DDX11 assays (see Figure 1C).
	0.69	Tim/Timeless, a member of the replication fork protection complex, operates with the Warsaw breakage syndrome DNA helicase DDX11 in the same fork recovery pathway
	0.68	Tim and DDX11 displayed a shortened tract length that was comparable to Tim depletion alone.
	0.66	Tim and DDX11 did not result in an additive effect on reduction of restarted DNA replication forks upon HU treatment suggesting an epistatic relationship between the two proteins in the forks rescue process in stressful conditions (see Figure 7C).
	0.64	DDX11 was used alone or in the presence of two amounts of Tim.
	0.61	DDX11 helicase activity was measured in the presence of increasing amounts of recombinant Tim (0.15, 0.3, 0.6, 1.2, 2.4, 4.8 pmol; lanes 4-9).
	0.61	Tim enhances DDX11 DNA binding and ATPase activity
	0.61	Tim- and/or DDX11-depleted cells.
	0.60	DDX11 from cell extracts as a consequence of RNAi-dependent downregulation of Tim.
	0.58	Tim and/or DDX11 in HeLa cells on the replication fork progression by DNA fiber track assays.
	0.56	DDX11 in the absence and presence of Tim using radiolabeled forked duplex or anti-parallel bimolecular G4 or three-stranded D-loop DNA structures (see Figure 4A-C).
	0.54	DDX11 polyclonal antibodies bound to Protein A agarose beads, revealed that endogenous Tim interacts with DDX11 (see Figure 5C).
	0.52	Tim and DDX11 operate in concert in the same cellular pathway required for efficient progression of DNA replication forks in perturbed S-phase conditions.
	0.51	DDX11 with Tim. (A) Surface plasmon resonance measurements were carried out to analyze the interaction of DDX11 with Tim using a Biacore2000 instrument.
	0.51	Tim (but not Tipin) is able to enhance the DNA helicase activity of DDX11 on structurally diverse DNA substrates.
30303954	0.98	Timeless was normalized to pulled down Flag-tagged DDX11 in each sample.
	0.98	DDX11-Timeless interaction is critical for chromosomal cohesion even in interphase nuclei.
	0.98	DDX11 promotes stable association of cohesin to chromatin during S phase in a way that is dependent on its direct interaction with Timeless.
	0.97	DDX11 helicase-dead mutants (K50R and Q23A), but not by the Timeless-binding defective mutants (KAE and KAK) (S6 Fig).
	0.97	DDX11, cohesin (Smc3 subunit; binding of Smc1 is shown in S8A Fig), Timeless and the Mcm4 protein.
	0.96	DDX11 residues responsible for Timeless binding, we carried out an analysis based on tiling peptide microarrays that covered the entire length of the DDX11 sequence.
	0.96	DDX11 KAK and KAE mutants and Timeless is not completely abolished in whole cell extracts, additional protein factors could mediate DDX11:Timeless interaction in vivo.
	0.96	DDX11 with Timeless is needed for proper sister chromatid cohesion.
	0.95	DDX11 with Timeless is critical for sister chromatid cohesion.
	0.95	DDX11 sequence (amino acid residues 1-906) were probed with (on left) or without (control micro-array on right) recombinant purified Flag-tagged Timeless and detected with a mixture of Cy3-labelled anti-Flag antibody and Cy5-labelled anti-HA antibody.
	0.95	DDX11 acts in concert with Timeless to ensure stable binding of cohesin to the advancing replisomes.
	0.95	Timeless may act upstream of DDX11 to enable a stable association of cohesin rings to the DNA replication forks.
	0.92	DDX11 peptides interacting with Timeless are reported on left.
	0.91	DDX11 Timeless-binding sites.
	0.91	DDX11 amino acid changes strongly reduced Timeless binding in human cells (Fig 1E).
	0.90	Timeless was normalized to pulled down Flag-tagged DDX11 in each sample.
	0.87	DDX11 wild type and mutant proteins and found that association of DDX11 KAE and KAK mutants to various components of the DNA replication machinery (such as Timeless, WDHD1 and Cdc45) was noticeably reduced relatively to the wild type protein (S8B Fig).
	0.87	Timeless and DDX11, including WDHD1 and RPA.
	0.86	DDX11 reduced the amount of cohesin that was co-immunoprecipitated with Cdc45, but had no effect on the pull-down of Mcm4 and Timeless (Figs 4C and S8A).
	0.82	Timeless-binding defective and helicase-dead mutants of DDX11 in complementation studies, we were able to demonstrate that the interaction of DDX11 with Timeless is more critical for sister chromatid cohesion than its DNA helicase activity.
	0.78	DDX11 DNA helicase that is responsible for the direct interaction with Timeless, a component of the replication fork-protection complex.
	0.71	DDX11 mutants with impaired Timeless-binding capability we found a reduced association of either DDX11 or cohesin to the DNA replication machinery (Figs 5 and S8).
	0.67	DDX11 KAE and KAK mutants with the endogenous Timeless was examined by co-immuno-precipitation experiments performed on whole extracts of HEK 293T cells ectopically expressing these DDX11 mutant forms.
	0.54	DDX11 and Timeless directly interact and operate in the same pathway that preserves replication fork progression in stressful conditions (such as dNTP depletion).
	0.51	DDX11 mutants defective in Timeless binding are unable to rescue sister chromatid cohesion defects of DDX11-depleted HeLa cells.
23797032	0.98	Timeless depletion leads to cohesion defects, which was alleviated by overexpression of ChlR1.
	0.97	Timeless protein, which plays a central role in the maintenance of the replication fork, interacts with ChlR1 in human cells.
	0.97	ChlR1- or Timeless-depleted cells showed growth rates similar to control cells (Fig 1B).
	0.97	Timeless, which interacts with ChlR1, is required for stable association of cohesin subunits with chromatin.
	0.97	Timeless or ChlR1 was efficiently downregulated.
	0.96	ChlR1 interacts with several replication fork proteins including PCNA, Fen1 and Timeless, it is straightforward to suggest that ChlR1's functions are required at the replication fork during S-phase.
	0.95	Timeless- and ChlR1-depleted cells have defects in efficient repair of DSBs, leading to accumulation of DNA damage.
	0.94	ChlR1/Chl1 also interacts with replication fork proteins such as PCNA and Fen1, our findings suggested that Timeless and ChlR1 work together at the replication fork to maintain replication fork structures and promote efficient sister chromatid cohesion.
	0.86	Timeless and ChlR1-depleted cells when compared to control cells (Fig 3A, Fig S2C).
	0.75	Timeless or ChlR1 was efficiently downregulated.
30469382	0.98	DDX11 to interact with the nucleic acid substrate in the presence of Timeless.
	0.97	DDX11 was shown to work jointly with Timeless in these genome integrity maintenance processes.
	0.97	DDX11 directly interacts with Timeless through a conserved peptide (the E200-Y201-E202 motif, located between helicase box I and Ia) (Figure 3) and this interaction is critical for a stable association of cohesin to the replication forks and for chromosomal cohesion in S, G2 and M phase.
	0.97	DDX11 N-terminal insertion between helicase boxes I and Ia (residues 65-225), which also contains the E200-Y201-E202 motif critical for the interaction with Timeless (Figure 3).
	0.96	Timeless was shown to establish a direct physical interaction with DDX11 and to stimulate its DNA helicase activity on diverse DNA substrates, including forked DNA substrates, bimolecular anti-parallel G4 and three-stranded D-loop structures (Figure 2).
	0.93	DDX11 in preserving replication fork integrity under stressful conditions was highlighted in a study performed in collaboration by the Pisani and Brosh groups, where it was reported that DDX11 and Timeless physically and functionally interact and act in concert to assist replisome smooth progression in hydroxyurea-treated HeLa cells.
	0.90	DDX11 binding sites for HPV E2 and Timeless are distinct or overlap and if Timeless influences the DDX11:E2 protein interaction in any way during the HPV life cycle.
	0.85	DDX11 and Timeless were found to be epistatic in promoting efficient resumption of stalled DNA replication forks after a prolonged treatment of HeLa cells with hydroxyurea.
	0.60	DDX11, between motifs I and Ia; the region in DDX11 that has been shown to interact with Timeless (in magenta) is located within this insertion.
	0.56	Timeless enhances DDX11 binding to DNA.
27636994	0.98	DDX11 and Tipin affect cohesion via a common pathway, and Tim directly interacts with DDX11.
	0.96	Tim (also known as Timeless) and Tipin, and the DDX11/ChlR1 helicase.
	0.96	Tim-Tipin fork protection complex, DDX11 helicase and ESCO2 acetyltransferase collaborate in several respects relevant for chromosome structure and genome integrity.
	0.92	DDX11 and Tim-Tipin are individually needed to compensate for ESCO2 loss in chromosome segregation, with DDX11 also playing complementary roles with ESCO2 in centromeric cohesion.
22987152	0.98	ChlR1 is reduced in Timeless depleted cells, it is possible that Timeless effectively recruits ChlR1 to promote lagging-strand synthesis (Fig. 1).
	0.97	Timeless modulates ChlR1 and Fen1 functions to facilitate lagging-strand synthesis, while Timeless also holds cohesin subunits on chromatin via protein-protein interaction, which, in turn, coordinates lagging-strand synthesis with SCC (Fig. 1).
	0.96	Timeless coimmunoprecipitates with ChlR1; Timeless is involved in loading of ChlR1 onto chromatin; and ChlR1 overexpression partially rescues SCC defects due to Timeless or Tipin depletion.
24487782	0.98	Timeless-Tipin on replication forks may allow ChlR1 to maintain its proper association with chromatin, whereby ChlR1-catalyzed DNA unwinding and protein interactions with factors that process lagging strand intermediates enable newly replicated sister chromatids to undergo appropriate cohesion.
	0.97	Timeless-Tipin and ChlR1 from cell-based experiments: (1) RNAi-depletion of Timeless resulted in reduction of ChlR1 protein levels, suggesting that Timeless helps to stabilize ChlR1 or maintain its association with chromatin where ChlR1 is more stable; and (2) exogenous overexpression of ChlR1 reduced cohesion defects caused by RNAi-depletion of Timeless or its associated partner Tipin, suggesting that ChlR1 cooperates with Timeless-Tipin to maintain proper sister chromatid cohesion.
	0.92	Timeless-Tipin in replication fork stabilization and sister chromatid cohesion, and found that, in human cells, Timeless-Tipin is not only associated with cohesion subunits (Smc1, Smc3, SA1) known to be important for sister chromatid cohesion but also with ChlR1.
32120966	0.98	DDX11 with the replication fork-protection factor Timeless is important for fork recovery from replication stress and promotion of sister chromatid cohesion.
	0.96	Timeless as a checkpoint protein that couples cell cycle progression with circadian rhythm raises the question if DDX11 or other DNA helicases implicated in the DNA damage response and genome maintenance are involved in the cell-autonomous clock that regulates physiologic functions.
32071282	0.96	DDX11 has been shown to co-localise with sites of DNA synthesis and to interact with proteins found at the replication fork, such as proliferating cell nuclear antigen (PCNA), FEN1, and Timeless.
	0.95	DDX11 interaction partners, namely, PCNA, Timeless, and FEN1, which all play a role in lagging-strand DNA replication, rendering a function of DDX11 in this context highly likely.
30700033	0.95	DDX11 interacts with Timeless, a core component of the eukaryotic replisome, potentially placing it in an ideal position to 'sweep' G4s that inhibit progression of the replicative polymerases.
27477908	0.92	DDX11 and several of its interacting partners, such as TIMELESS, ESPL1, and components of the minichromosome maintenance complex (MCM) (Figure S2H).