Regulation of the initiation of DNA replication in human cells

Moiseeva, Tatiana N.; Bakkenist, Christopher J.

doi:10.1016/j.dnarep.2018.09.003

Cited by 39 publications

(40 citation statements)

References 115 publications

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“…CDC7 kinase and CDKs are the two master S-phase-promoting factors that control origin activation. It is well established that CDKs regulate origin firing with CDK-dependent phosphorylation events regulating origin licensing and usage (reviewed in [57,58]). At the same time, CDKs control the activity of enzymes required for dealing with replication stress, including the CtIP and EXO1 nucleases and the MRN complex [59,60].…”

Section: Discussionmentioning

confidence: 99%

CDC7 kinase promotes MRE11 fork processing, modulating fork speed and chromosomal breakage

et al. 2020

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The CDC7 kinase is essential for the activation of DNA replication origins and has been implicated in the replication stress response. Using a highly specific chemical inhibitor and a chemical genetic approach, we now show that CDC7 activity is required to coordinate multiple MRE11-dependent processes occurring at replication forks, independently from its role in origin firing. CDC7 localizes at replication forks and, similarly to MRE11, mediates active slowing of fork progression upon mild topoisomerase inhibition. Both proteins are also retained on stalled forks, where they promote fork processing and restart. Moreover, MRE11 phosphorylation and localization at replication factories are progressively lost upon CDC7 inhibition. Finally, CDC7 activity at reversed forks is required for their pathological MRE11-dependent degradation in BRCA2deficient cells. Thus, upon replication interference CDC7 is a key regulator of fork progression, processing and integrity. These results highlight a dual role for CDC7 in replication, modulating both initiation and elongation steps of DNA synthesis, and identify a key intervention point for anticancer therapies exploiting replication interference.

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Section: Discussionmentioning

confidence: 99%

CDC7 kinase promotes MRE11 fork processing, modulating fork speed and chromosomal breakage

et al. 2020

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“…This is in line with recent studies using inhibitors of the upstream kinase ATR, the kinase that activates Chk1. ATR inhibitors synergize with radiotherapy in mouse models by suppressing PD-L1 expression and reducing amounts of T regulatory cells promoting anti-tumor immunity (2). Trials combining ATR inhibitors and PD-1 inhibitors are on the way (e.g.…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Small molecule inhibitors and a kinase-dead expressing mouse model demonstrate that the kinase activity of Chk1 is essential for mouse embryos and cancer cells

Muralidharan

Nilsson

Lindberg

et al. 2020

Preprint

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Chk1 kinase is downstream of the ATR kinase in the sensing of improper replication. Previous cell culture studies have demonstrated that Chk1 is essential for replication and Chk1 inhibitors are efficacious against tumors with high-level replication stress such as Myc-induced lymphoma cells. Treatment with Chk1 inhibitors also combines well with certain chemotherapeutic drugs and effects associates with induction of DNA damage and reduction of Chk1 protein levels. Most studies of Chk1 function has relied on the use of inhibitors. Whether or not a mouse or cancer cells could survive if a kinase-dead form of Chk1 is expressed has not been investigated before. Here we generate a mouse model that expresses a kinase-dead (D130A) allele in the mouse germline. We find that this mouse is overtly normal and does not have problems with erythropoiesis with ageing as previously been shown for a mouse expressing one null allele. However, similar to a null allele, homozygous kinase-dead mice cannot be generated and timed pregnancies of heterozygous mice suggest lethality of homozygous blastocysts at around the time of implantation. By breeding the kinasedead Chk1 mouse with a conditional allele we are able to demonstrate that expression of only one kinase-dead allele, but no wildtype allele, of Chek1 is lethal for Mycinduced cancer cells. Finally, treatment of melanoma cells with tumor-infiltrating T cells or CAR-T cells is effective even if Chk1 is inhibited, suggesting that Chk1 inhibitors can be safely administered in patients where immunotherapy is an essential component of the arsenal against cancer.

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“…Our data showing that anti-tumoral T-cell immunity is not affected by Chk1 inhibitors are in line with recent studies using inhibitors of the upstream kinase ATR, the kinase that activates Chk1. ATR inhibitors synergize with radiotherapy in mouse models by suppressing PD-L1 expression and reducing amounts of T regulatory cells promoting antitumor immunity (2). Trials combining ATR inhibitors and PD-1 inhibitors are on the way (e.g., NCT04095273).…”

Section: Discussionmentioning

confidence: 99%

“…Replication is tightly controlled to ensure accurate copying of the large DNA molecule (1). Not only the initiation of replication but also the progression of the replication fork is regulated by kinases (2). If the cell experiences replication stress, UV-induced DNA damage, and enzymatic and helicase remodeling after DNA inter-strand cross-linking chemotherapy or environmental agents, the replication fork is stalled (3).…”

Section: Introductionmentioning

confidence: 99%

Small molecule inhibitors and a kinase-dead expressing mouse model demonstrate that the kinase activity of Chk1 is essential for mouse embryos and cancer cells

et al. 2020

View full text Add to dashboard Cite

Chk1 kinase is downstream of the ATR kinase in the sensing of improper replication. Previous cell culture studies have demonstrated that Chk1 is essential for replication. Indeed, Chk1 inhibitors are efficacious against tumors with high-level replication stress such as Myc-induced lymphoma cells. Treatment with Chk1 inhibitors also combines well with certain chemotherapeutic drugs, and effects associate with the induction of DNA damage and reduction of Chk1 protein levels. Most studies of Chk1 function have relied on the use of inhibitors. Whether or not a mouse or cancer cells could survive if a kinase-dead form of Chk1 is expressed has not been investigated before. Here, we generate a mouse model that expresses a kinase-dead (D130A) allele in the mouse germ line. We find that this mouse is overtly normal and does not have problems with erythropoiesis with aging as previously been shown for a mouse expressing one null allele. However, similar to a null allele, homozygous kinase-dead mice cannot be generated, and timed pregnancies of heterozygous mice suggest lethality of homozygous blastocysts at around the time of implantation. By breeding the kinase-dead Chk1 mouse with a conditional allele, we are able to demonstrate that expression of only one kinase-dead allele, but no wild-type allele, of Chek1 is lethal for Myc-induced cancer cells. Finally, treatment of melanoma cells with tumor-infiltrating T cells or CAR-T cells is effective even if Chk1 is inhibited, suggesting that Chk1 inhibitors can be safely administered in patients where immunotherapy is an essential component of the arsenal against cancer.

show abstract

Regulation of the initiation of DNA replication in human cells

Cited by 39 publications

References 115 publications

CDC7 kinase promotes MRE11 fork processing, modulating fork speed and chromosomal breakage

CDC7 kinase promotes MRE11 fork processing, modulating fork speed and chromosomal breakage

Small molecule inhibitors and a kinase-dead expressing mouse model demonstrate that the kinase activity of Chk1 is essential for mouse embryos and cancer cells

Small molecule inhibitors and a kinase-dead expressing mouse model demonstrate that the kinase activity of Chk1 is essential for mouse embryos and cancer cells

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