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23 major scientific news

Scientific news

DNA damage: repair adapted in space

According to the location of damaged genes in the nucleus, the cell is able to trigger different and adapted repair mechanisms.

Nuclear position dictates DNA repair pathway choice.

Lemaître C(1), Grabarz A(1), Tsouroula K(1), Andronov L(1), Furst A(1), Pankotai T(1), Heyer V(1), Rogier M(1), Attwood KM(2), Kessler P(1), Dellaire G(2), Klaholz B(1), Reina-San-Martin B(1), Soutoglou E(1).

Genes Dev Nov. 15, 2014

Nov. 3, 2014

The double-strand DNA breaks are particularly dangerous. The research team of Evi Soutoglou at IGBMC has just discovered that the choice of natural repair mechanisms of the cell, in response to this type of injury, depends on the location of genes in the nucleus. These results are published on the 3rd of November in the journal Genes & Development.

DNA repair
Our body is continuously subjected to endogenous and environmental factors that can affect its integrity and cause DNA damage. The double-strand breaks (DSBs) on DNA are particularly critical and can cause cancer. The cell is happily fitted with multiple systems to detect and repair these damages. More or less effective, their use notably depends on when the lesion occurs during the cell cycle. Before dividing the cell replicates its DNA. During replication, DNA is copied to produce two sister chromatids. There are at least two major types of repair of DSBs, based on completely different mechanisms. Homologous recombination (HR) uses a DNA sequence identical to the damaged one (the sister chromatid) for reconstructing the missing DNA piece. But this mechanism can only be used when DNA is replicated. On the other hand, the non-homologous end joining (NHEJ) repair system directly bonds the two ends of the lesion. It has the advantage of being able to take place throughout the cell cycle. In parallel to this path, a less accurate alternative end joining (A-EJ) mechanism has also been described in the absence of NHEJ, but the mechanisms of its control are still unknown.


Tell me where you are, I'll tell you how you will be repaired
Depending on the stage of the cell cycle, but also its location in the nucleus, the chromatin (form under which DNA is packed) is more or less compact. Knowing that cellular DNA is not randomly stored in the nucleus, Evi Soutoglou’s team became interested in the influence of DNA  location in the nucleus on the type of repair triggered. While it is usually HR or NHEJ that are set off inside the nucleus, the researchers showed that the lesions on genes located near the nuclear envelope resulted exclusively in NHEJ or A-EJ mechanisms. This is also the first time that the A-EJ path is shown in physiological conditions where NHEJ is functional. These results are explained by the fact that many repeats of the same gene are present in the nuclear periphery, and triggering  HR would increase the risk of using the wrong sequence in place of the sister chromatid. In addition, the high degree of compaction of DNA at this location prevents the recruitment of the proteins responsible for the HR, inhibiting this mechanism. Finally, as genes located on the periphery of the nucleus are generally not expressed, an error in the repair related to the use of A-EJ would not have dramatic consequence.


These results show for the first time a segregation of mechanisms of DSB repair, depending on the location of the targeted genes in the nucleus. They also provide new insights into the mechanism of A-EJ repair, unexplored so far.

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