DNA double strand break repair pathway choice: a chromatin based decision?

Abstract

DNA double-strand breaks (DSBs) are highly toxic lesions that can be rapidly repaired by 2 main pathways, namely Homologous Recombination (HR) and Non Homologous End Joining (NHEJ). The choice between these pathways is a critical, yet not completely understood, aspect of DSB repair. We recently found that distinct DSBs induced across the genome are not repaired by the same pathway. Indeed, DSBs induced in active genes, naturally enriched in the trimethyl form of histone H3 lysine 36 (H3K36me3), are channeled to repair by HR, in a manner depending on SETD2, the major H3K36 trimethyltransferase. Here, we propose that these findings may be generalized to other types of histone modifications and repair machineries thus defining a "DSB repair choice histone code". This "decision making" function of preexisting chromatin structure in DSB repair could connect the repair pathway used to the type and function of the damaged region, not only contributing to genome stability but also to its diversity.

Keywords: DNA double strand breaks; DSB pathway choice; chromatin, trimethyl H3K36; homologous recombination.

Figure 1.

Preexistent chromatin structure influences DSB repair. (A) Actively transcribed genes are enriched for the transcription elongation mark H3K36me3 (red circles) by the action of SETD2 associating with elongating RNA Pol II. Histone acetylation on H4K16 (H4K16ac, yellow circles) is also enriched on active transcription units. Upon DSB induction, LEDGF-mediated CtIP recruitment, via H3K36me3 recognition, will favor resection and channel repair toward HR. H4K16ac will impede 53BP1 accumulation near DSBs, which will favor resection and BRCA1 dependent repair. (B) Condensed heterochromatin is characterized by H3K9me3 enrichment (gray trapezoids), the histone mark bound by HP1 via its chromodomain. Following DSBs, HP1 is evicted, allowing for Tip60 to interact with H3K9me3 through its own chromodomain. Tip60-dependant acetylation will favor chromatin remodeling and nucleosome removal, and probably resection, required for HR repair of DSB occurring in heterochromatin. (C) H4K20 mono and dimethylation (blue circles) are abundant modifications in mammalian genomes. Upon DSB, H4K20me1/2 is unmasked, via L3MBTL1 eviction or KDM4A degradation, DSB induced structural changes or histone modifications such as H2AK15ub (purple squares). This favors 53BP1 recruitment near the break sites, inhibits resection, allowing DSB repair by NHEJ.

Figure 2.

Potential mechanisms for preexistent chromatin structure in addressing repair pathways. (A) Following DSB and initial recognition by end binding proteins, such as Ku or the MRN complex, chromatin modifications already present at the break will stabilize component of a specific DNA repair pathway and/or inhibit association of component from another pathway. (B) DSB induces unmasking of existing histone marks by chromatin structure remodeling and/or chromatin reader eviction, making these modifications available for recognition by DNA repair factors. (C) In undamaged chromatin, repair proteins may preferentially interact with certain region of the genome based on their specific chromatin signature, facilitating their loading upon DSB induction.