Am J Cancer Res 2012;2(3):249-268
Review Article
Initiation of DNA double strand break repair: signaling and single-stranded
resection dictates the choice between homologous recombination,
non-homologous end-joining and alternative end-joining
Anastazja Grabarz*, Aurélia Barascu*, Josée Guirouilh-Barbat, Bernard S Lopez
Université Paris Sud, Laboratoire « Stabilité Génétique et Oncogenèse » CNRS, UMR 8200 and Institut de Cancérologie
Gustave-Roussy, PR2, 114 Rue Edouard Vaillant, 94805 VILLEJUIF. CNRS, France. *These authors equally contributed to this
work.
Received April 3, 2012; accepted April 15, 2012; Epub April 21, 2012; Published May 15, 2012
Abstract: A DNA double strand break (DSB) is a highly toxic lesion, which can generate genetic instability and profound genome
rearrangements. However, DSBs are required to generate diversity during physiological processes such as meiosis or the
establishment of the immune repertoire. Thus, the precise regulation of a complex network of processes is necessary for the
maintenance of genomic stability, allowing genetic diversity but protecting against genetic instability and its consequences on
oncogenesis. Two main strategies are employed for DSB repair: homologous recombination (HR) and non-homologous
end-joining (NHEJ). HR is initiated by single-stranded DNA (ssDNA) resection and requires sequence homology with an intact
partner, while NHEJ requires neither resection at initiation nor a homologous partner. Thus, resection is an essential step for
DSB repair initiation, driving the choice of the DSB repair pathway employed. However, an alternative end-joining (A-EJ) pathway,
which is highly mutagenic, has recently been described; A-EJ is initiated by ssDNA resection but does not require a homologous
partner. The choice of the appropriate DSB repair system, for instance according the cell cycle stage, is essential for genome
stability maintenance. In this context, controlling the initial events of DSB repair is thus an essential step that may be irreversible,
and the wrong decision should lead to dramatic consequences. Here, we first present the main DSB repair mechanisms and
then discuss the importance of the choice of the appropriate DSB repair pathway according the cell cycle phase. In a third
section, we present the early steps of DSB repair i.e., DSB signaling, chromatin remodeling, and the regulation of ssDNA
resection. In the last part, we discuss the competition between the different DSB repair mechanisms. Finally, we conclude with
the importance of the fine tuning of this network for genome stability maintenance and for tumor protection in
fine.(AJCR00000113).
Keywords: DNA double strand break, Homologous recombination, Non homologous end joining, alternative end-joining,
Resection, chromatin remodeling, genetic instability, genome rearrangements
Address all correspondence to:
Dr. Bernard S Lopez
Université Paris Sud, Laboratoire « Stabilité Génétique et Oncogenèse » CNRS
UMR 8200 and Institut de Cancérologie Gustave-Roussy
PR2, 114 Rue Edouard Vaillant, 94805 VILLEJUIF. CNRS, France.
E-mail: Bernard.Lopez@igr.fr
Review Article
Initiation of DNA double strand break repair: signaling and single-stranded
resection dictates the choice between homologous recombination,
non-homologous end-joining and alternative end-joining
Anastazja Grabarz*, Aurélia Barascu*, Josée Guirouilh-Barbat, Bernard S Lopez
Université Paris Sud, Laboratoire « Stabilité Génétique et Oncogenèse » CNRS, UMR 8200 and Institut de Cancérologie
Gustave-Roussy, PR2, 114 Rue Edouard Vaillant, 94805 VILLEJUIF. CNRS, France. *These authors equally contributed to this
work.
Received April 3, 2012; accepted April 15, 2012; Epub April 21, 2012; Published May 15, 2012
Abstract: A DNA double strand break (DSB) is a highly toxic lesion, which can generate genetic instability and profound genome
rearrangements. However, DSBs are required to generate diversity during physiological processes such as meiosis or the
establishment of the immune repertoire. Thus, the precise regulation of a complex network of processes is necessary for the
maintenance of genomic stability, allowing genetic diversity but protecting against genetic instability and its consequences on
oncogenesis. Two main strategies are employed for DSB repair: homologous recombination (HR) and non-homologous
end-joining (NHEJ). HR is initiated by single-stranded DNA (ssDNA) resection and requires sequence homology with an intact
partner, while NHEJ requires neither resection at initiation nor a homologous partner. Thus, resection is an essential step for
DSB repair initiation, driving the choice of the DSB repair pathway employed. However, an alternative end-joining (A-EJ) pathway,
which is highly mutagenic, has recently been described; A-EJ is initiated by ssDNA resection but does not require a homologous
partner. The choice of the appropriate DSB repair system, for instance according the cell cycle stage, is essential for genome
stability maintenance. In this context, controlling the initial events of DSB repair is thus an essential step that may be irreversible,
and the wrong decision should lead to dramatic consequences. Here, we first present the main DSB repair mechanisms and
then discuss the importance of the choice of the appropriate DSB repair pathway according the cell cycle phase. In a third
section, we present the early steps of DSB repair i.e., DSB signaling, chromatin remodeling, and the regulation of ssDNA
resection. In the last part, we discuss the competition between the different DSB repair mechanisms. Finally, we conclude with
the importance of the fine tuning of this network for genome stability maintenance and for tumor protection in
fine.(AJCR00000113).
Keywords: DNA double strand break, Homologous recombination, Non homologous end joining, alternative end-joining,
Resection, chromatin remodeling, genetic instability, genome rearrangements
Address all correspondence to:
Dr. Bernard S Lopez
Université Paris Sud, Laboratoire « Stabilité Génétique et Oncogenèse » CNRS
UMR 8200 and Institut de Cancérologie Gustave-Roussy
PR2, 114 Rue Edouard Vaillant, 94805 VILLEJUIF. CNRS, France.
E-mail: Bernard.Lopez@igr.fr
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American Journal of Cancer Research
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