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Related Concept Videos

Homologous Recombination02:31

Homologous Recombination

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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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Conservative Site-specific Recombination and Phase Variation02:53

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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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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,...
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Long-patch Base Excision Repair01:02

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Since the discovery of the two BER pathways, there has been a debate about how a cell chooses one pathway over the other and the factors determining this selection. Numerous in vitro experiments have pointed out multiple determinants for the sub-pathway selection. These are:
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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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Base Excision Repair01:54

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One of the common DNA damages is the chemical alteration of single bases by alkylation, oxidation, or deamination. The altered bases cause mispairing and strand breakage during replication. This type of damage causes minimal change to the DNA double helix structure and can be repaired by the base excision repair (BER) pathways. BER corrects damaged DNA sequences by removing the damaged base and restoring the original base sequence using the complementary strand as a template.
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Related Experiment Video

Updated: Jun 11, 2025

Detection of Homologous Recombination Intermediates via Proximity Ligation and Quantitative PCR in Saccharomyces cerevisiae
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53BP1 deficiency leads to hyperrecombination using break-induced replication (BIR).

Sameer Bikram Shah1, Youhang Li1,2, Shibo Li1,3

  • 1Department of Molecular and Cell Biology, The Scripps Research Institute, La Jolla, CA, 92037, USA.

Nature Communications
|October 5, 2024
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Summary

53BP1 suppresses mutagenic break-induced replication (BIR) by preventing DNA synthesis on single-stranded overhangs. Loss of 53BP1 activates BIR, leading to genomic instability and offering cancer treatment targets.

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Area of Science:

  • Molecular Biology
  • Genetics
  • Cancer Research

Background:

  • Break-induced replication (BIR) is a mutagenic DNA repair pathway.
  • The regulation of BIR and its role in double-strand break (DSB) repair remain poorly understood.
  • 53BP1 is known for its role in DSB end protection.

Purpose of the Study:

  • To investigate the role of 53BP1 in suppressing BIR.
  • To elucidate the mechanisms governing BIR regulation and DSB repair pathway selection.
  • To explore the therapeutic potential of targeting the interplay between 53BP1 and BIR.

Main Methods:

  • Investigated 53BP1's function in suppressing BIR at DSBs.
  • Analyzed BIR-like hyperrecombination in 53BP1-deficient cells.
  • Examined the role of Polα-primase, PCNA ubiquitination, and PIF1 in BIR activation.
  • Studied 53BP1's function on broken replication forks involving SMARCAD1.

Main Results:

  • Loss of 53BP1 induces BIR-like hyperrecombination dependent on Polα-primase.
  • 53BP1 deficiency leads to PCNA ubiquitination and PIF1 recruitment, activating BIR.
  • SMARCAD1 displaces 53BP1 on broken forks to facilitate BIR activation.
  • 53BP1 deficiency results in template switching and large deletions, contributing to genome instability.

Conclusions:

  • 53BP1 plays a critical role in suppressing BIR after end resection at DSBs, distinct from its end protection role.
  • The interplay between 53BP1 and BIR pathways offers synthetic lethality, presenting opportunities for targeted cancer therapy.
  • Understanding 53BP1's function in BIR regulation is key to preventing genome instability.