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

Abstract

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.

Defects in homologous recombination repair behind the human diseases: FA and HBOC

“…The EMSY locus is amplified in sporadic breast cancer (13%) and higher-grade ovarian cancer (17%). At the cellular level, EMSY overexpression leads to defective HR (Cousineau & Belmaaza 2011), consistent with the notion that the EMSY-binding region of BRCA2 is likely to coincide or overlap with the PALB2-interacting region.…”

“…This region of BRCA2 was also reported to bind to EMSY (HughesDavies et al 2003). The EMSY-binding region of BRCA2 is encoded by exon 3, which is known to be deleted in cancer (Hughes-Davies et al 2003, Cousineau & Belmaaza 2011. The EMSY locus is amplified in sporadic breast cancer (13%) and higher-grade ovarian cancer (17%).…”

EMSY promoted the growth and migration of ovarian cancer cells

“…Multiple studies have confirmed the functional link between BRCA2 and EMSY [5][6][7]. EMSY was found to inactivate the function of BRCA2, leading to the development of sporadic breast and ovarian cancers [8,9].…”

The protein kinase Akt1 regulates the interferon response through phosphorylation of the transcriptional repressor EMSY

“…It binds BRCA2, but not BRCA1, through the EMSY N-terminal (ENT) domain. Although the function of EMSY has not been extensively investigated, existing evidence suggests that it may contribute to chromatin modification, DNA repair, and transcription (10,11). EMSY was found to colocalize with BRCA2 on dsDNA breaks.…”