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Related Concept Videos

Fixing Double-strand Breaks02:04

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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...
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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...
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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...
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Updated: Oct 3, 2025

Characterizing DNA Repair Processes at Transient and Long-lasting Double-strand DNA Breaks by Immunofluorescence Microscopy
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Immediate-Early, Early, and Late Responses to DNA Double Stranded Breaks.

Shaylee R Kieffer1, Noel F Lowndes1

  • 1Centre for Chromosome Biology (CCB), Biomedical Sciences Building (BSB), School of Biological and Chemical Sciences, National University of Ireland, Galway (NUIG), Galway, Ireland.

Frontiers in Genetics
|February 17, 2022
PubMed
Summary

Cellular responses to DNA double strand breaks (DSBs) are categorized into Immediate-Early, Early, and Late phases, each involving distinct sensing and repair mechanisms to maintain genomic integrity. Understanding these complex pathways is crucial for comprehending genome stability and mutagenesis.

Keywords:
DNA repairEarly responseImmediate-early responseLate responsedouble strand breaks (DSBs)homologous recombination (HR)non-homologous end joining (NHEJ)pre-repair responses

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Area of Science:

  • Molecular Biology
  • Genetics
  • Cell Biology

Background:

  • DNA double-strand breaks (DSBs) are severe DNA lesions that can lead to genomic instability if not repaired correctly.
  • Cellular responses to DSBs are critical for maintaining genomic integrity and preventing mutations.
  • Existing models categorize DSB repair responses, but a nuanced understanding of the temporal and mechanistic aspects is needed.

Purpose of the Study:

  • To define and differentiate the Immediate-Early, Early, and Late pre-repair response phases to DNA double-strand breaks (DSBs).
  • To elucidate the molecular players and mechanisms involved in each response phase, including sensing, recruitment, and pathway choice.
  • To highlight the importance of these coordinated responses in preserving genomic integrity and preventing mutagenesis.

Main Methods:

  • Conceptual framework based on analogy with viral infection response dynamics.
  • Integration of existing knowledge on key proteins like PARPs, KU70/80, MRN, ATM, 53BP1, and BRCA1.
  • Analysis of DSB processing, chromatin dynamics, and pathway selection mechanisms (e.g., cNHEJ, HR).

Main Results:

  • The Immediate-Early response involves rapid lesion sensing (PARPs, KU70/80, MRN) and fast-kinetic canonical non-homologous end joining (cNHEJ), independent of foci formation.
  • The Early response is characterized by ATM-dependent recruitment of signaling molecules into large, visible foci, involving complex chromatin dynamics.
  • The Late response integrates cellular context to determine repair pathway choice (slow-kinetic cNHEJ or HR), critically involving 53BP1 and BRCA1 recruitment.

Conclusions:

  • The temporal categorization of DSB responses into Immediate-Early, Early, and Late phases provides a framework for understanding complex DNA repair regulation.
  • Dysregulation or loss of components in these pathways can lead to increased mutagenesis due to reliance on alternative repair mechanisms.
  • Further characterization of recruited factors throughout the DSB response is necessary to fully understand pathway choice determination.