The Friedman Lab

Welcome!

The Friedman laboratory is interested in mechanisms that maintain genome stability, with research endeavors that lie at the intersection of DNA replication and DNA repair.

The Friedman lab is recruiting rotation students for 2026-2027! Please contact Dr. Friedman for more information.

Telomeres: The ends of chromosomes (telomeres) constitute a tiny fraction of DNA in a cell, but play a central role in genome stability and cellular lifespan. Processing of the leading strand results in chromosome shortening following conventional replication. A ribonucleoprotein enzyme, telomerase, replenishes these terminal sequences. Since the catalytic subunit of telomerase is not expressed in most human somatic cells, human chromosomes lose telomere sequence upon successive cell divisions, a process that limits proliferative capacity. DNA loss is reversed in the vast majority of cancers by reactivation of telomerase, allowing cells to far exceed their normal life expectancy. Since inhibition of telomerase triggers apoptosis or senescence of some tumor cell lines, telomerase is a promising target of anti-cancer therapy. Genetic experiments initiated two decades ago established the yeast Saccharomyces cerevisiae as a key model system for studies of telomerase. Furthermore, conservation of several telomerase components between yeast and human suggests that many aspects of yeast telomere biology have correlates in human cells. The ease with which the cell cycle can be manipulated and the vast array of genetic approaches make yeast an ideal system in which to study mechanisms and consequences of telomerase regulation at the cellular level.

Telomerase and double-strand breaks: Genome integrity is fundamentally important for human health as mutations can lead to cancer and inherited disease. Mutation frequency is not uniform across the genome as some DNA sequences present a high risk of damage or engage at increased frequency with error-prone repair pathways. Interstitial telomere-like sequences fall into the latter category by stimulating the formation of a new, or de novo, telomere at a double-strand break (DSB). Telomeres, the repetitive, protein-bound DNA sequences at chromosome ends, promote genome stability by protecting linear chromosomes from degradation and facilitating replication through recruitment of telomerase. In contrast, addition of a de novo telomere at an internal site precludes normal repair and causes loss of all sequences distal to the break. The consequences of de novo telomere addition (dnTA) are evident in diseases such as Phelan McDermid syndrome and alpha-thalassemia where the occurrence of multiple independent mutations is consistent with presence of a destabilizing DNA sequence.

Our prior work characterized hotspots of dnTA in the yeast genome termed SiRTAs (Sites of Repair-associated Telomere Addition). SiRTAs stimulate dnTA events even when the initiating DSB is located several kilobases distal to the eventual site of telomere addition, demonstrating that SiRTAs are destabilizing due to their engagement of telomerase, rather than intrinsic fragility. We recently identified UBP10, encoding a ubiquitin protease, as a positive regulator of dnTA. Upon closer inspection, we find that nonreciprocal translocations dramatically increase at SiRTAs in the mutant background. This novel and unanticipated result implies that SiRTAs engage multiple error-prone repair pathways and that repair pathway choice is modulated by ubiquitin. Intriguingly, SiRTAs are disproportionately impacted by the loss of UBP10 and translocations formed at SiRTAs predominantly involve the subtelomeric repeats. These events resemble those facilitating survival of cancer cells in the absence of telomerase [a recombination-mediated pathway termed alternative lengthening of telomeres (ALT)]. We are leveraging these unique observations to understand how intrinsically destabilizing sequences impact genome stability and to explore the mechanisms and regulation of error-prone DNA repair.