Endogenous as well as radiation-induced DSBs provoke a DNA damage response characterized by the activation and recruitment of ATM (Ataxia Telangiectasia mutated) leading to the phosphorylation of Ser-139 of histone H2AX molecules adjacent to break sites.
The 200 kb breakage zone at ABL contains translocation break sites distributed anywhere between alternative exons 1a and 1b.
These findings are consistent with the hypothesis that SETD2-dependent H3K36me3 promotes recruitment of CtIP by LEDGF to break sites.
Interestingly, we found that two of five genes, namely RAD51C and NOCA3, have DNA break sites within the gene body region.
Genetic studies were recently conducted on the RAD51 paralogs, involved in the same DNA repair pathway: BRCA2 protein loads RAD51 monomers at DNA double-strand break sites; RAD51 recruitment also depends on the RAD51 paralog family [ 13].
Two subsequent studies noted that knockdown of SIRT6 in human cells similarly sensitized the cells to chemically induced DSBs, and also observed that SIRT6 is recruited to break sites after DNA damage [ 21, 22].
The VCP (valosine-containing protein), a chaperone protein that regulates ubiquitin-dependent protein degradation, is phosphorylated by DNA-PK and recruited to DNA double-strand break sites to regulate DNA damage repair.
The SWI/SNF complex is involved in DNA repair, DNA synthesis, and genomic stability since it has been shown to target the chromatin at DNA double-strand break sites.
This mechanism would result in origins migrating to break sites rather than existing prior to breakage, thereby leading to origins being found at sites that are the product of an evolutionary rearrangement.
In addition, the KDM2A H3K36 demethylase is phosphorylated by ATM kinase in response to double-strand breaks and, instead of recruiting KDM2A to break sites, phosphorylation abrogates its chromatin-binding activity.
If stalled forks are not restarted in a timely fashion, it could result in fork collapse, formation of double strand breaks and activation of the DNA damage response, which involves recruitment of ATM and ATR (damage-activated sensor kinases) to break sites and activation of the intra-S-phase checkpoint [ 25, 26].
