EMSY overexpression disrupts the BRCA2/RAD51 pathway in the DNA-damage response: implications for chromosomal instability/recombination syndromes as checkpoint diseases

EMSY links the BRCA2 pathway to sporadic breast/ovarian cancer. It encodes a nuclear protein that binds to the BRCA2 N-terminal domain implicated in chromatin/transcription regulation, but when sporadically amplified/overexpressed, increased EMSY level represses BRCA2 transactivation potential and induces chromosomal instability, mimicking the activity of BRCA2 mutations in the development of hereditary breast/ovarian cancer. In addition to chromatin/transcription regulation, EMSY may also play a role in the DNA-damage response, suggested by its ability to localize at chromatin sites of DNA damage/repair. This implies that EMSY overexpression may also repress BRCA2 in DNA-damage replication/checkpoint and recombination/repair, coordinated processes that also require its interacting proteins: PALB2, the partner and localizer of BRCA2; RPA, replication/checkpoint protein A; and RAD51, the inseparable recombination/repair enzyme. Here, using a well-characterized recombination/repair assay system, we demonstrate that a slight increase in EMSY level can indeed repress these two processes independently of transcriptional interference/repression. Since EMSY, RPA and PALB2 all bind to the same BRCA2 region, these findings further support a scenario wherein: (a) EMSY amplification may mimic BRCA2 deficiency, at least by overriding RPA and PALB2, crippling the BRCA2/RAD51 complex at DNA-damage and replication/transcription sites; and (b) BRCA2/RAD51 may coordinate these processes by employing at least EMSY, PALB2 and RPA. We extensively discuss the molecular details of how this can happen to ascertain its implications for a novel recombination mechanism apparently conceived as checkpoint rather than a DNA repair system for cell division, survival, death, and human diseases, including the tissue specificity of cancer predisposition, which may renew our thinking about targeted therapy and prevention

Regulation of DSB Repair by Cell-cycle Signaling and the DNA Damage Response

Of the many types of DNA lesions, DNA double-strand breaks (DSBs) are considered the most harmful, because one unrepaired DSB is sufficient to trigger permanent growth arrest and cell death. In addition, DSBs are potent inducers of gross chromosomal rearrangements such as deletions, translocations and amplifications. DSB signalling and repair through different pathways is crucial to preserve genomic integrity and maintain cellular homeostasis. Therefore, it is no wonder if the cell finely regulates DSB repair pathways in the different cell cycle phases and following activation of the DNA damage checkpoint. In this short essay we will illustrate some known aspects of the regulation of DSB repair in the mitotic cell cycle. In particular we will focus on the balance of the two main DSB repair pathways: NHEJ, non-homologous end joining and H(D)R, homologous (directed) recombination, as well as on the regulation of the resolution of joint molecules that arise during H(D)R