Post-Translational Modifications of the Mini-Chromosome Maintenance Proteins in DNA Replication

Li, Zheng; Xu, Xingzhi

doi:10.3390/genes10050331

Cited by 46 publications

(33 citation statements)

References 157 publications

(183 reference statements)

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“…6b, d, e). In addition, there were chromosomes (14,15) in which the DONSON and FANCM signals were intermingled ( Supplementary Fig. 6f, g).…”

Section: Association Of Donson and Fancm With Genomic Sequencesmentioning

confidence: 99%

“…These include alternate DNA structures, protein: DNA adducts, DNA covalent modifications introduced by exogenous or endogenous reactants, depleted nucleotide precursor pools, etc. Replication stress activates the ATR (ATM-and Rad3-related) kinase, with hundreds of substrates, including MCM proteins 13,14 , and stimulates the recruitment of numerous factors to stalled replication forks 15,16 . These function in a variety of pathways to relieve obstacles, reconstruct broken forks, and restart replication.…”

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confidence: 99%

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DONSON and FANCM associate with different replisomes distinguished by replication timing and chromatin domain

et al. 2020

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Duplication of mammalian genomes requires replisomes to overcome numerous impediments during passage through open (eu) and condensed (hetero) chromatin. Typically, studies of replication stress characterize mixed populations of challenged and unchallenged replication forks, averaged across S phase, and model a single species of "stressed" replisome. Here, in cells containing potent obstacles to replication, we find two different lesion proximal replisomes. One is bound by the DONSON protein and is more frequent in early S phase, in regions marked by euchromatin. The other interacts with the FANCM DNA translocase, is more prominent in late S phase, and favors heterochromatin. The two forms can also be detected in unstressed cells. ChIP-seq of DNA associated with DONSON or FANCM confirms the bias of the former towards regions that replicate early and the skew of the latter towards regions that replicate late.

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“…6b, d, e). In addition, there were chromosomes (14,15) in which the DONSON and FANCM signals were intermingled ( Supplementary Fig. 6f, g).…”

Section: Association Of Donson and Fancm With Genomic Sequencesmentioning

confidence: 99%

mentioning

confidence: 99%

DONSON and FANCM associate with different replisomes distinguished by replication timing and chromatin domain

et al. 2020

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“…Budding yeast Mcm10 is di-ubiquitinated during S phase, permitting recognition by PCNA ( 44 ). However, it remains unclear whether human MCM10 undergoes similar modifications, and whether such modifications regulate its function, even though two forms of human MCM10 whose gel migration corresponds to mono- and diubiquitinated species can be detected in late G1 and through S phase ( 45 , 46 ). In G1-synchronised cells (5 h after nocodazole release), a slow-migrating form of MCM10 suggestive of a di-ubiquitinated species is not detected on chromatin, consistent with the absence of PCNA recruitment on chromatin before S phase initiation (Figure 4D and E ).…”

Section: Resultsmentioning

confidence: 99%

A kinase-independent function for AURORA-A in replisome assembly during DNA replication initiation

Almeida

Renaudin

Venkitaraman

2020

Nucleic Acids Research

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Abstract The catalytic activity of human AURORA-A kinase (AURKA) regulates mitotic progression, and its frequent overexpression in major forms of epithelial cancer is associated with aneuploidy and carcinogenesis. Here, we report an unexpected, kinase-independent function for AURKA in DNA replication initiation whose inhibition through a class of allosteric inhibitors opens avenues for cancer therapy. We show that genetic depletion of AURKA, or its inhibition by allosteric but not catalytic inhibitors, blocks the G1-S cell cycle transition. A catalytically inactive AURKA mutant suffices to overcome this block. We identify a multiprotein complex between AURKA and the replisome components MCM7, WDHD1 and POLD1 formed during G1, and demonstrate that allosteric but not catalytic inhibitors prevent the chromatin assembly of functional replisomes. Indeed, allosteric but not catalytic AURKA inhibitors sensitize cancer cells to inhibition of the CDC7 kinase subunit of the replication-initiating factor DDK. Thus, our findings define a mechanism essential for replisome assembly during DNA replication initiation that is vulnerable to inhibition as combination therapy in cancer.

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“…6c). These proteins include critical regulators of chromosome decatenation and mitotic checkpoints for proper chromosome segregation such as DNA topoisomerase TOP2A and NCD80 62,63 ; MCM2, which promotes DNA replication 64 ; cell-cycle regulators SRPK1 and CDK1-3, which are serine-threonine protein kinases that regulate the G2-M transition and mitotic progression 65 ; and the cell-cycle inhibitor RB1, which regulates transcription and the G1-S transition and is repressed by phosphorylation 66 (Fig. 6d and Extended Data Fig.…”

Section: Ctdnep1 Post-translationally Modulates the Activities Of Key Regulators For Proper Chromosome Decatenation And Mitotic Checkpoinmentioning

confidence: 99%

Loss of nuclear envelope phosphatase CTDNEP1 drives aggressive medulloblastoma by triggering MYC amplification and genomic instability

Luo

Liao

Xin

et al. 2021

Preprint

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MYC-driven medulloblastomas are highly aggressive childhood brain tumors, however, the genetic events triggering MYC amplification and malignant transformation remain elusive. Here we report that mutations in CTDNEP1, a CTD nuclear-envelope-phosphatase, are the most significantly enriched recurrent alterations in MYC-driven medulloblastomas, and define high-risk subsets with poorer prognosis. CTDNEP1 ablation transforms murine cerebellar progenitors into MYC-amplified medulloblastomas, resembling their human counterparts. CTDNEP1 deficiency stabilizes MYC protein by elevating MYC serine-62 phosphorylation, and triggers genomic instability with eventual MYC amplification and p53 loss. Further, phosphoproteomics reveals that CTDNEP1 post-translationally modulates the activities of key regulators for proper chromosome segregation and mitotic checkpoints including topoisomerase TOP2A and checkpoint kinase CHEK1. Co-targeting CHEK1 and MYC activities synergistically inhibits CTDNEP1-deficient MYC-amplified tumor growth and prolongs animal survival. Together, our studies identify CTDNEP1 acting as a tumor suppressor in highly aggressive medulloblastomas by maintaining homeostatic MYC levels and genomic stability, highlighting a CTDNEP1-dependent therapeutic vulnerability.

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Post-Translational Modifications of the Mini-Chromosome Maintenance Proteins in DNA Replication

Cited by 46 publications

References 157 publications

DONSON and FANCM associate with different replisomes distinguished by replication timing and chromatin domain

DONSON and FANCM associate with different replisomes distinguished by replication timing and chromatin domain

A kinase-independent function for AURORA-A in replisome assembly during DNA replication initiation

Loss of nuclear envelope phosphatase CTDNEP1 drives aggressive medulloblastoma by triggering MYC amplification and genomic instability

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