Environmental Factor, June 2011, National Institute of Environmental Health Sciences
LMG speaker explores BRCA signaling network
By Eddy Ball
Genome instability is a hallmark of cancer, Greenberg explained, leading "to the hypothesis that genome integrity through DNA damage responses was necessary for tumor suppression." (Photo courtesy of Roger Greenberg)
Understanding genomic instability early on may offer insight into the many factors involved in cancer, according to biologist Roger Greenberg, M.D., Ph.D. Greenberg's talk May 2 at NIEHS, "Relationship of Chromatin Responses to DNA Repair and Tumor Suppression," was hosted by Intramural Research Training Award Fellow Steven Roberts, Ph.D.(http://www.niehs.nih.gov/research/atniehs/labs/lmg/cs/staff.cfm), as part of the NIEHS Laboratory of Molecular Genetics (LMG) Fellows Invited Lecture Series.
Greenberg(http://www.med.upenn.edu/apps/faculty/index.php/g5455356/p8145566) is an assistant professor of cancer biology and assistant investigator in the Abramson Family Cancer Research Institute at the University of Pennsylvania (Penn) School of Medicine Institute for Translational Medicine and Therapeutics. He and his group at Penn investigate the molecular events that contribute to inherited breast and ovarian cancer predisposition, particularly the role of the breast and ovarian cancer suppressor protein BRCA1 in biochemical pathways involved in DNA double strand break (DSB) repair.
A family of factors involved in familial cancers
Single nucleotide polymorphisms (SNPs) of BRCA1 and BRCA2, first identified in the 1990s by groups that included NIEHS scientists, explain some cases of breast cancer. But Greenberg is convinced that the causes of more than half of familial breast cancers involve anomalies in at least 13 different tumor repressors that interact with BRCA1 and constitute a BRCA1-centered breast and ovarian tumor suppressor network. Individuals harboring these SNPs presumably have compromised DNA repair capabilities leading to further gene mutations and epigenetic alterations that contribute to tumor development in response to endogenous metabolic events and environmental exposures, including oncogenic viruses and ionizing radiation. Better understanding what goes awry in the BRCA1-centered tumor suppressor network, Greenberg maintains, could lead to interventions to prevent or reverse processes that allow tumor formation and proliferation.
Under normal conditions, Greenberg explained, the breast cancer gene BRCA1 helps orchestrate the repair of damaged DNA. When the BRCA1 gene is mutated or the network goes haywire with mutations of genes encoding BRCA1-interacting proteins, a woman's vulnerability to breast or ovarian cancer rises because the rate at which genes are altered increases. These errors in the BRCA1-center tumor suppressor network inhibit the recruitment of repair complexes to DNA damage sites.
Greenberg has found interactions among BRCA1 and a number of proteins in the recognition of DNA damage. Most are familiar to scientists in the field of molecular genetics, such as ubiquitin, which is instrumental in post-translational modification, RAD51, Abraxas, BRCC36, RNF8, and MDC1. Two relatively new players, both ubiquitin-interacting proteins - RAP80, which was discovered by the group headed by NIEHS Principal Investigator Anton Jetten, Ph.D., and the Greenberg group's own discovery, MERIT40 - have also been shown to strongly influence BRCA1 function.
From DSBs to epigenetic modification of chromatin
Mutations and genetic alterations, such as translocations, are often thought of as the main drivers of cancer. However, Greenberg believes other cellular changes may be important as well. "Not only are there genetic changes in the early stages of cancer," Greenberg said, "but there are chromatin changes as well here, as seen in the phosphorylation of the histone H2A variant, gamma-H2aX."
In recent experiments, the Greenberg lab has demonstrated a further link between the generation of DSBs and alterations in chromatin structure. His group has recently published evidence that DSBs induce an ATM kinase-dependent transcriptional silencing that spans multiple kilobases of chromatin in cis to the site of DNA damage. He explained that the interplay between chromatin structure and DNA repair influences diverse biological phenomena, including cellular senescence and viral latency, that are part of the molecular basis underlying epigenetic changes that occur during carcinogenesis.
Not surprisingly, given the complexity of the BRCA1 signaling network, Greenberg remains cautious about progress. However, as his experiments have demonstrated, DSB-induced silencing can be reversed, pointing the way to other potential interventions to manipulate DNA damage response and restore DSB repair efficiency and balance. One intriguing development in new work from the Greenberg group is the potential of the protein ICP0, which promotes transcription of latent herpes simplex virus, to effectively reverse DSB-induced silencing when expressed.