Checkpoint Responses to DNA Double-Strand Breaks

David P Waterman1, James E Haber1, Marcus B Smolka2

  • 1Department of Biology and Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, Massachusetts 02454, USA;

Insights

Cells activate a DNA damage checkpoint (DDC) to repair DNA double-strand breaks (DSBs). This response prevents cell death and cancer by halting the cell cycle and initiating DNA repair, studied in yeast and mammals.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • Cells encounter DNA damage, including DNA double-strand breaks (DSBs), during each cell cycle.
  • Unrepaired or improperly repaired DSBs can lead to cell lethality or cancer.
  • The DNA damage checkpoint (DDC) response is a critical cellular mechanism to manage DSBs.

Purpose of the Study:

  • To examine the DNA damage checkpoint (DDC) response induced by DNA double-strand breaks (DSBs).
  • To investigate the conserved mechanisms of DDC in both budding yeast and mammalian systems.

Main Methods:

  • Comparative analysis of DDC pathways.
  • Utilizing budding yeast as a model organism.
  • Investigating DDC in mammalian cells.

Main Results:

  • The DDC response involves cell cycle arrest, gene expression reprogramming, and recruitment of DNA repair factors.
  • Conserved elements of the DDC response exist between yeast and mammals.
  • The DDC is essential for preventing the inheritance of damaged chromosomes.

Conclusions:

  • The DNA damage checkpoint is a fundamental cellular process for maintaining genomic integrity.
  • Understanding DDC mechanisms in model systems like yeast can provide insights into human disease, including cancer.
  • The study highlights the conserved nature of DNA damage response pathways across eukaryotes.

Related Concept Videos

Homologous Recombination02:31

Homologous Recombination

The basic reaction of homologous recombination (HR) involves two chromatids that contain DNA sequences sharing a significant stretch of identity. One of these sequences uses a strand from another as a template to synthesize DNA in an enzyme-catalyzed reaction. The final product is a novel amalgamation of the two substrates. To ensure an accurate recombination of sequences, HR is restricted to the S and G2 phases of the cell cycle. At these stages, the DNA has been replicated already and the...
62.0K
Fixing Double-strand Breaks02:04

Fixing Double-strand Breaks

The double-stranded structure of DNA has two major advantages. First, it serves as a safe repository of genetic information where one strand serves as the back-up in case the other strand is damaged. Second, the double-helical structure can be wrapped around proteins called histones to form nucleosomes, which can then be tightly wound to form chromosomes. This way, DNA chains up to 2 inches long can be contained within microscopic structures in a cell. A double-stranded break not only damages...
14.1K
Fixing Double-strand Breaks02:04

Fixing Double-strand Breaks

4.1K
DNA Damage Can Stall the Cell Cycle02:36

DNA Damage Can Stall the Cell Cycle

In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
3.0K
DNA Damage can Stall the Cell Cycle02:36

DNA Damage can Stall the Cell Cycle

In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
9.9K
Restarting Stalled Replication Forks02:37

Restarting Stalled Replication Forks

DNA replication is initiated at sites containing predefined DNA sequences known as origins of replication. DNA is unwound at these sites by the minichromosome maintenance (MCM) helicase and other factors such as Cdc45 and the associated GINS complex.The unwound single strands are protected by replication protein A (RPA) until DNA polymerase starts synthesizing DNA at the 5’ end of the strand in the same direction as the replication fork. To prevent the replication fork from falling apart,...
6.2K