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Double-strand breaks cause genomic instability and are thus potentially lethal to cells. They also greatly increase the risk of cancer and the chance of chromosome structural mutations. Compare and contrast the two mechanisms of double-strand break repair. Why would one mechanism be used over another

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Answer:

DNA double-strand breaks are repaired by two main pathways( routes):  

i) Non-homologous end joining and  

ii) homologous recombination .

Explanation:

All organisms suffer by double-strand breaks (DSBs) in their DNA.

DSBs  caused by  exposure to exogenous agents such as radiations, also by certain chemicals, and through endogenous processes, including DNA replication and repair.

Double-strand break repair:

The processing and repair of DSBs can lead to mutations, they can also lead to loss of heterozygosity, and chromosome rearrangements that can result into cell death or cancer.

DNA double-strand breaks are repaired by two main pathways( routes):  

i) Non-homologous end joining and  

ii) homologous recombination .

Homologous recombination- it takes place by means of replication, using the homologous strand as template. Homologous recombination therefore requires extensive regions of DNA homology in another DNA duplex, and  there is no loss of genetic information normally.

Non-homologous end joining- It requires no homology with a second DNA duplex and no, or only a few base pairs of, homology between the two broken DNA ends.

Homologous recombination is the mainly preferred mechanism in yeast.

Non-homologous DNA end joining is more commonly mutagenic than  homologous recombination  repair.

Double strand break

Explanation:

Double strand break leads to genomic rearrangements and instability,two mechanisms of double-strand break repair are:

Homologous recombination:occurs between two DNA molecules and completed in following sequential steps:

  • Alignment of two homologous chromosomes
  • Strand invasion in DNA molecules
  • Each invading strand joins to the broken end of other DNA molecule creating a Holliday junction
  • Branch migration occurs
  • Rotation of bottom half strands of DNA molecule
  • The Holliday model predicts cross over or non cross over recombination DNA depends on whether cleavage is on vertical or horizontal plane
  • Cleavage in vertical plane produces cross over recombinant consisting of two heteroduplex DNA whereas horizontal cleavage gives non cross over recombinants

Non homologous end joining(NHEJ):

  • A heterodimer of KU70/KU80 binds to broken ends and recruit DNA PKCs (DNA dependent protein kinase catalytic subunit)
  • DNA PKCs recruit an enzyme called Artemis which has both exo and endonuclease activity that trims broken ends
  • DNA PKCs catalyse phosphorylation of Artemis that can remove 5' or 3' extension or hair pins that might be present at the ends
  • Artemis act as Flapp endonuclease and cleaves any unpaired segments
  • Small DNA gaps are filled by DNA Polymerase
  • Complex of DNA ligase IV with XRCC joins the broken ends to each other

Homologous recombination is considered a more accurate mechanism for double strand repair because broken ends use homologous sequences elsewhere in the genome (sister chromatids, homologous chromosomes, or repeated regions on the same or different chromosomes) to prime repair synthesis