DDK promotes DNA replication initiation: Mechanistic and structural insights

Li, Ningning; Gao, Ning; Zhai, Yuanliang

doi:10.1016/j.sbi.2022.102504

Cited by 8 publications

(3 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…DNA replication initiates from only a subset of these licensed origins, namely those where the helicase complex is activated, a process referred to as origin firing (Rhind and Gilbert 2013). Origin firing is triggered by activation of two kinase signaling pathways, DDK and CDK, which then cause each hexameric Mcm helicase to encircle a single strand of DNA and track in opposite directions in front of the replisome, thereby establishing bidirectional replication (Heller et al 2011; Larasati and Duncker 2016; Li et al 2023). Firing factors are not present in sufficient quantities to activate all licensed origins simultaneously, and thus origins are activated in waves, with firing factors being recycled until the entire genome has been replicated (Mantiero et al 2011; Tanaka et al 2011).…”

Section: Introductionmentioning

confidence: 99%

Sir2 and Fun30 regulate ribosomal DNA replication timing via MCM helicase positioning and nucleosome occupancy

Lichauco,

Foss,

Gatbonton-Schwager

et al. 2024

Preprint

View full text Add to dashboard Cite

The association between late replication timing and low transcription rates in eukaryotic heterochromatin is well-known, yet the specific mechanisms underlying this link remain uncertain. InSaccharomyces cerevisiae, the histone deacetylase Sir2 is required for both transcriptional silencing and late replication at the repetitive ribosomal DNA arrays (rDNA). We have previously reported that in the absence ofSIR2, a derepressed RNA PolII repositions MCM replicative helicases from their loading site at the ribosomal origin, where they abut well-positioned, high-occupancy nucleosomes, to an adjacent region with lower nucleosome occupancy. By developing a method that can distinguish activation of closely spaced MCM complexes, here we show that the displaced MCMs at rDNA origins have increased firing propensity compared to the non-displaced MCMs. Furthermore, we found that both, activation of the repositioned MCMs and low occupancy of the adjacent nucleosomes critically depend on the chromatin remodeling activity ofFUN30. Our study elucidates the mechanism by which Sir2 delays replication timing, and it demonstrates, for the first time, that activation of a specific replication originin vivorelies on the nucleosome context shaped by a single chromatin remodeler.

show abstract

Section: Introductionmentioning

confidence: 99%

Sir2 and Fun30 regulate ribosomal DNA replication timing via MCM helicase positioning and nucleosome occupancy

Lichauco,

Foss,

Gatbonton-Schwager

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Throughout G1, MCM2-7 complexes remain bound to chromatin but do not unwind the double-stranded DNA (dsDNA). Replication initiation occurs when MCMs are activated by two cell-cycle-dependent kinases, Dbf4-dependent kinase (DDK) and cyclindependent kinase (CDK) [14][15][16][17]. Phosphorylation of MCMs allows association of the helicase-activating components, GINS and Cdc45, that, together with MCM2-7, form the active CMG holo-helicase [18,19].…”

Section: Introductionmentioning

confidence: 99%

The MCM2-7 Complex: Roles beyond DNA Unwinding

Rankin,

Rankin

2024

Biology

View full text Add to dashboard Cite

The MCM2-7 complex is a hexameric protein complex that serves as a DNA helicase. It unwinds the DNA double helix during DNA replication, thereby providing the single-stranded replication template. In recent years, it has become clear that the MCM2-7 complex has additional functions that extend well beyond its role in DNA replication. Through physical and functional interactions with different pathways, it impacts other nuclear events and activities, including folding of the genome, histone inheritance, chromosome segregation, DNA damage sensing and repair, and gene transcription. Collectively, the diverse roles of the MCM2-7 complex suggest it plays a critical role in maintaining genome integrity by integrating the regulation of DNA replication with other pathways in the nucleus.

show abstract

“…ORC then serves as a platform to recruit two copies of Mcm2-7 complexes onto origin DNA as a head-to-head double hexamer (DH) encircling double-stranded DNA (dsDNA) 11 – 16 . Upon entering S phase, multiple origin-firing factors work in concert to convert the inert Mcm2-7 DH into two active replisomes 17 – 20 . First, Dbf4-dependent kinase Cdc7 (DDK) phosphorylates Mcm2/4/6 subunits to assemble Sld3-7 and Cdc45 onto the Mcm2-7 DH 21 – 26 .…”

Section: Introductionmentioning

confidence: 99%

Synergism between CMG helicase and leading strand DNA polymerase at replication fork

Xu,

Feng,

et al. 2023

Nat Commun

Self Cite

View full text Add to dashboard Cite

The replisome that replicates the eukaryotic genome consists of at least three engines: the Cdc45-MCM-GINS (CMG) helicase that separates duplex DNA at the replication fork and two DNA polymerases, one on each strand, that replicate the unwound DNA. Here, we determined a series of cryo-electron microscopy structures of a yeast replisome comprising CMG, leading-strand polymerase Polε and three accessory factors on a forked DNA. In these structures, Polε engages or disengages with the motor domains of the CMG by occupying two alternative positions, which closely correlate with the rotational movement of the single-stranded DNA around the MCM pore. During this process, the polymerase remains stably coupled to the helicase using Psf1 as a hinge. This synergism is modulated by a concerted rearrangement of ATPase sites to drive DNA translocation. The Polε-MCM coupling is not only required for CMG formation to initiate DNA replication but also facilitates the leading-strand DNA synthesis mediated by Polε. Our study elucidates a mechanism intrinsic to the replisome that coordinates the activities of CMG and Polε to negotiate any roadblocks, DNA damage, and epigenetic marks encountered during translocation along replication forks.

show abstract

DDK promotes DNA replication initiation: Mechanistic and structural insights

Cited by 8 publications

References 46 publications

Sir2 and Fun30 regulate ribosomal DNA replication timing via MCM helicase positioning and nucleosome occupancy

Sir2 and Fun30 regulate ribosomal DNA replication timing via MCM helicase positioning and nucleosome occupancy

The MCM2-7 Complex: Roles beyond DNA Unwinding

Synergism between CMG helicase and leading strand DNA polymerase at replication fork

Contact Info

Product

Resources

About