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Related Concept Videos

DNA Helicases00:55

DNA Helicases

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DNA unwinding helicase enzymes are a type of motor protein. Motor proteins can translocate along filaments or polymers using energy generated from ATP hydrolysis. Helicases are involved in all the important cellular processes where DNA unwinding is required, such as DNA replication, repair, recombination, and transcription. They are present in all living organisms, but vary in their structure, function, and mechanism of action. For example, in prokaryotes, DnaB helicase binds and translocates...
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The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
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Cancer is the second leading cause of death in the United States. A cancer cell is genetically unstable and hence can mutate faster. They can also modify their microenvironment and escape immune surveillance. The difficulties in treating cancer are further compounded by the emergence of rapid resistance to anticancer drugs. The most common ways to attain resistance in cancer cells include alteration in drug transport and metabolism, modification of drug target, elevated DNA damage response, or...
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The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
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Because the DNA segments are cut and reorganized in a direction-specific manner, site-specific recombination has emerged as an efficient genetic engineering technique. Flippase and Cyclization recombinases or Flp and Cre, respectively, are two members of the tyrosine recombinase family derived from bacteriophages, that are used to mediate site-specific DNA insertions, deletions, and targeted expression of proteins in mammalian cell lines.
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Identification of Selective ATP-Competitive CMG Helicase Inhibitors for Cancer Intervention that Disrupt

Shengyan Xiang1,2, Xingju Luo1,2, Darcy Welch1,3

  • 1Cancer Biology and Evolution Program, Moffitt Cancer Center and Research Institute, Tampa, FL 33612.

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Summary

Researchers identified novel CMG helicase inhibitors (CMGi) that selectively target cancer cells. These compounds disrupt DNA replication and cell growth by inhibiting CMG ATPase and helicase activities, offering a new anti-cancer therapeutic strategy.

Keywords:
CMG helicaseCdc45DNA replicationGINSMCMaminocoumarin

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • The CMG helicase (Cdc45-MCM-GINS) is crucial for DNA replication and presents a potential anti-cancer target due to tumor-specific vulnerabilities.
  • Oncogenic alterations and replicative stress (e.g., chemotherapy) highlight CMG's essential role in cancer cell survival and recovery.

Approach:

  • Developed an orthogonal biochemical screening method to identify selective CMG inhibitors (CMGi).
  • Utilized structure-activity relationship analysis and in silico docking to understand CMGi binding within MCM subunits.
  • Investigated the molecular mechanisms by which CMGi inhibit CMG helicase activity and impact DNA replication.

Key Points:

  • Identified CMGi that inhibit CMG helicase ATPase and helicase activities via ATP-competitive binding at low micromolar concentrations.
  • CMGi bind to MCM ATP sites and channels, likely interfering with ATP/ADP exchange.
  • CMGi disrupt CMG assembly, including MCM ring formation and GINS recruitment, and destabilize the replisome by causing Cdc45/GINS dissociation.

Conclusions:

  • CMGi induce DNA damage by disrupting replisome integrity and interactions with key replication factors.
  • These novel CMGi exhibit selective toxicity towards tumor cells.
  • Defined a new class of CMG helicase-targeted anti-cancer compounds with unique mechanisms of action.